CA2721785A1 - New arylsulphonylglycine derivatives, the preparation thereof and their use as medicaments - Google Patents
New arylsulphonylglycine derivatives, the preparation thereof and their use as medicaments Download PDFInfo
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- CA2721785A1 CA2721785A1 CA2721785A CA2721785A CA2721785A1 CA 2721785 A1 CA2721785 A1 CA 2721785A1 CA 2721785 A CA2721785 A CA 2721785A CA 2721785 A CA2721785 A CA 2721785A CA 2721785 A1 CA2721785 A1 CA 2721785A1
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract
The invention relates to substituted aryl-sulphonylglycine derivatives of general formula (I) wherein the groups R a to R f, A and Z are defined as in the specification and claims, which are suitable for preparing a pharmaceutical composition for the treatment of metabolic disorders, particularly type 1 or type 2 diabetes mellitus.
Description
New arylsuiphonyiglycine derivatives, the preparation thereof and their use as medicaments The present invention relates to new substituted arylsulphonylglycine derivatives of general formula Rd Re A
a A" I /IA
R\ O A
O TA AA f N R
O
Rb O ~I) Z
RC
wherein the groups Ra to Rf, A and Z are defined as hereinafter, including the tautomers, stereoisomers, mixtures thereof and salts thereof. This invention further relates to medicaments containing a compound of formula (I) according to the invention as well as the use of a compound according to the invention for preparing a medicament for the treatment of metabolic disorders, particularly type 1 or type 2 diabetes mellitus. The invention also relates to processes for preparing a medicament as well as a compound according to the invention.
Compounds of formula (I) are suitable for preventing the inhibiting effect of glycogen phosphorylase on the activity of glycogen synthase by stopping the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1). Compounds with these properties stimulate glycogen synthesis and are proposed for the treatment of metabolic disorders, particularly diabetes (P. Cohen, Nature Reviews Molecular Cell Biology 2006, 7, 867-874).
Aim of the invention The aim of the present invention is to provide new arylsulphonylamino-methylphosphonic acid derivatives that suppress the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase (PP1).
A further aim of the present invention is to provide new pharmaceutical compositions that are suitable for the prevention and/or treatment of metabolic disorders, particularly diabetes.
Another aim of this invention is to provide a process for preparing the compounds according to the invention.
Other aims of the present invention will become directly apparent to the skilled man from the foregoing remarks and those that follow.
Object of the invention In a first aspect the present invention relates to new substituted arylsulphonylglycine derivatives of general formula:
Rd Re A
a ~A
R\ O I O *AAA\sA
f N R
O
Rb O (I) Z
RC
In the above formula (I) Ra denotes H, a group of formula o-~
or a C1_6-alkyl group, which may be substituted by Cl_6-alkyl-carbonyloxy, Cl_6-alkoxy-carbonyloxy, Cl_6-alkoxy, hydroxy, amino, aminocarbonyl or amino-C2.3-alkyloxy, wherein in each case one or two of the hydrogen atoms present on the nitrogen may be replaced independently of one another by a C1_3-alkyl group, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkyloxy or heterocycloalkyl-Ci _3-al kyloxy, Rb and Rc each independently of one another denotes H, halogen, C1_3-alkyl, C2.3-alkenyl, C2.3-alkynyl, Cl_3-perfluoroalkyl, Cl_3-alkoxy, Cl_3-perfluoroalkoxy, while in each case only one of the groups Rb and Rc may represent H, A denotes CH or N, while a total of not more than four nitrogen atoms may be present in the bicyclic system, Z denotes CH, CF or N, Rd and Re independently of one another denote H, halogen, cyano, hydroxy, nitro, C1_6-alkyl, C2.6-alkenyl, C2.6-alkynyl, C1_6-fluoroalkyl, C1_6-perfluoroalkyl, C3.7-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1_6-alkoxy, C1_6-fluoroalkoxy, Ci_6-perfluoroalkoxy, C3_7-cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, C1_6-alkylsulphanyl, C3_7-cycloalkylsulphanyl or a group selected from among R'R2N, R'R2N-CO, R'R2N-CO-NR3, R' R2N-SO, R' R2N-S02, R' R2N-S02-NR3, R4-CO, R4-CO-NR3, R5-SO, R5-SO-NR3, R5-SO2, R5-SO2-NR3-and R5-CO-O-, wherein R1 denotes H, Ci_6-alkyl, C3_7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R2 denotes H, Ci_6-alkyl, C3_7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R3 denotes H, C1_6-alkyl or C3_7-cycloalkyl, R4 denotes C1.6-alkyl, C3_7-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, or C1.6-alkyloxy and R5 denotes C1.6-alkyl, C3_7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and Rf denotes H, halogen, C1.3-alkyl, C2.3-alkenyl, C2.3-alkynyl, C1.3-perfluoroalkyl, C1.3-alkoxy, C1.3-perfluoroalkoxy or cyano, while the groups contained in the C1.6-alkyl, C2.6-alkenyl, C2.6-alkynyl, C3_7-cycloalkyl, C1.6-alkyloxy and C3_7-cycloalkyloxy groups mentioned hereinbefore for Rd, Re, Rf as well as R' to R5 may each be di- or trisubstituted independently of one another in the carbon skeleton by a group selected from among cyano, hydroxy, C3_7-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1.6-alkoxy, C1.6-perfluoroalkoxy, C3_7-cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy and a group selected from among R6R7N, R6R7N-CO, R6R7N-CO-NR8, R6R7N-S02-NR8, R9-CO, R9-CO-NR8, R10-SO2, R10-SO2-NR 8- and R10-CO-O, wherein R6 denotes H, C1.4-alkyl, C3.6-cycloalkyl, C3.6-cycloalkyl-C1.4-alkyl, heterocycloalkyl, heterocycloalkyl-C1.4-alkyl, aryl, aryl-C1.4-alkyl, heteroaryl or heteroaryl-C1.4-alkyl, R7 denotes H, C1.4-alkyl, C3.6-cycloalkyl, C3.6-cycloalkyl-C1.4-alkyl, heterocycloalkyl, heterocycloalkyl-C1.4-alkyl, aryl, aryl-C1.4-alkyl, heteroaryl or heteroaryl-C1.4-alkyl, R8 denotes H, C1.4-alkyl, C3.6-cycloalkyl or C3.6-cycloalkyl-C1.4-alkyl, R9 denotes C1.4-alkyl, C3.6-cycloalkyl, C3.6-cycloalkyl-C1.4-alkyl, heterocycloalkyl, heterocycloalkyl-Cl-4-alkyl, aryl, aryl-Cl-4-alkyl, heteroaryl, heteroaryl-Cl-4-alkyl, hydroxy or C1-4-alkyloxy and R10 denotes C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-Cl-4-alkyl, 5 heterocycloalkyl, heterocycloalkyl-Cl-4-alkyl, aryl, aryl-Cl-4-alkyl, heteroaryl or heteroaryl-Cl-4-alkyl, while the above-mentioned substituents must not be bound to a common carbon atom and heteroatoms must be separated from one another by at least two carbon atoms, and the aryl, heteroaryl, aryloxy and heteroaryloxy groups contained in the groups mentioned hereinbefore for Rd, Re as well as R1 to R5 may each be di- or trisubstituted independently of one another in the carbon skeleton by a group selected from among halogen, cyano, hydroxy, nitro, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-Cl-4-alkyl, C1-6-perchloroalkyl, C1-6-fluoroalkyl, perfluoroalkyl, C1-6-alkoxy, C1-6-fluoroalkoxy, C1-6-perfluoroalkoxy, C3-7-cyclo-alkyloxy, C3-7-cycloalkyl-Cl-4-alkyloxy, heterocycloalkyloxy, heterocycloalkyl-C1-4-alkyloxy C1-6-alkylsulphanyl, C3-7-cycloalkylsulphanyl, and a group selected from among R6R7N, R6R'N-CO, R6R7N-CO-NR8, R6R7N-SO, R6R7N-S02, R6R7N-S02-NR8, R9-CO, R9-CO-NR8, R10-SO, R10-SO-NR8, R10-S02, R10-SO2-NR 8- and R10-CO-O, while R6 to R10 are as hereinbefore defined.
The invention also relates to the tautomers, stereoisomers, mixtures and salts, particularly the physiologically acceptable salts, of the compounds according to the invention.
The compounds of general formula (I) according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, in particular they suppress the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1).
a A" I /IA
R\ O A
O TA AA f N R
O
Rb O ~I) Z
RC
wherein the groups Ra to Rf, A and Z are defined as hereinafter, including the tautomers, stereoisomers, mixtures thereof and salts thereof. This invention further relates to medicaments containing a compound of formula (I) according to the invention as well as the use of a compound according to the invention for preparing a medicament for the treatment of metabolic disorders, particularly type 1 or type 2 diabetes mellitus. The invention also relates to processes for preparing a medicament as well as a compound according to the invention.
Compounds of formula (I) are suitable for preventing the inhibiting effect of glycogen phosphorylase on the activity of glycogen synthase by stopping the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1). Compounds with these properties stimulate glycogen synthesis and are proposed for the treatment of metabolic disorders, particularly diabetes (P. Cohen, Nature Reviews Molecular Cell Biology 2006, 7, 867-874).
Aim of the invention The aim of the present invention is to provide new arylsulphonylamino-methylphosphonic acid derivatives that suppress the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase (PP1).
A further aim of the present invention is to provide new pharmaceutical compositions that are suitable for the prevention and/or treatment of metabolic disorders, particularly diabetes.
Another aim of this invention is to provide a process for preparing the compounds according to the invention.
Other aims of the present invention will become directly apparent to the skilled man from the foregoing remarks and those that follow.
Object of the invention In a first aspect the present invention relates to new substituted arylsulphonylglycine derivatives of general formula:
Rd Re A
a ~A
R\ O I O *AAA\sA
f N R
O
Rb O (I) Z
RC
In the above formula (I) Ra denotes H, a group of formula o-~
or a C1_6-alkyl group, which may be substituted by Cl_6-alkyl-carbonyloxy, Cl_6-alkoxy-carbonyloxy, Cl_6-alkoxy, hydroxy, amino, aminocarbonyl or amino-C2.3-alkyloxy, wherein in each case one or two of the hydrogen atoms present on the nitrogen may be replaced independently of one another by a C1_3-alkyl group, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkyloxy or heterocycloalkyl-Ci _3-al kyloxy, Rb and Rc each independently of one another denotes H, halogen, C1_3-alkyl, C2.3-alkenyl, C2.3-alkynyl, Cl_3-perfluoroalkyl, Cl_3-alkoxy, Cl_3-perfluoroalkoxy, while in each case only one of the groups Rb and Rc may represent H, A denotes CH or N, while a total of not more than four nitrogen atoms may be present in the bicyclic system, Z denotes CH, CF or N, Rd and Re independently of one another denote H, halogen, cyano, hydroxy, nitro, C1_6-alkyl, C2.6-alkenyl, C2.6-alkynyl, C1_6-fluoroalkyl, C1_6-perfluoroalkyl, C3.7-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1_6-alkoxy, C1_6-fluoroalkoxy, Ci_6-perfluoroalkoxy, C3_7-cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, C1_6-alkylsulphanyl, C3_7-cycloalkylsulphanyl or a group selected from among R'R2N, R'R2N-CO, R'R2N-CO-NR3, R' R2N-SO, R' R2N-S02, R' R2N-S02-NR3, R4-CO, R4-CO-NR3, R5-SO, R5-SO-NR3, R5-SO2, R5-SO2-NR3-and R5-CO-O-, wherein R1 denotes H, Ci_6-alkyl, C3_7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R2 denotes H, Ci_6-alkyl, C3_7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R3 denotes H, C1_6-alkyl or C3_7-cycloalkyl, R4 denotes C1.6-alkyl, C3_7-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, or C1.6-alkyloxy and R5 denotes C1.6-alkyl, C3_7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and Rf denotes H, halogen, C1.3-alkyl, C2.3-alkenyl, C2.3-alkynyl, C1.3-perfluoroalkyl, C1.3-alkoxy, C1.3-perfluoroalkoxy or cyano, while the groups contained in the C1.6-alkyl, C2.6-alkenyl, C2.6-alkynyl, C3_7-cycloalkyl, C1.6-alkyloxy and C3_7-cycloalkyloxy groups mentioned hereinbefore for Rd, Re, Rf as well as R' to R5 may each be di- or trisubstituted independently of one another in the carbon skeleton by a group selected from among cyano, hydroxy, C3_7-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1.6-alkoxy, C1.6-perfluoroalkoxy, C3_7-cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy and a group selected from among R6R7N, R6R7N-CO, R6R7N-CO-NR8, R6R7N-S02-NR8, R9-CO, R9-CO-NR8, R10-SO2, R10-SO2-NR 8- and R10-CO-O, wherein R6 denotes H, C1.4-alkyl, C3.6-cycloalkyl, C3.6-cycloalkyl-C1.4-alkyl, heterocycloalkyl, heterocycloalkyl-C1.4-alkyl, aryl, aryl-C1.4-alkyl, heteroaryl or heteroaryl-C1.4-alkyl, R7 denotes H, C1.4-alkyl, C3.6-cycloalkyl, C3.6-cycloalkyl-C1.4-alkyl, heterocycloalkyl, heterocycloalkyl-C1.4-alkyl, aryl, aryl-C1.4-alkyl, heteroaryl or heteroaryl-C1.4-alkyl, R8 denotes H, C1.4-alkyl, C3.6-cycloalkyl or C3.6-cycloalkyl-C1.4-alkyl, R9 denotes C1.4-alkyl, C3.6-cycloalkyl, C3.6-cycloalkyl-C1.4-alkyl, heterocycloalkyl, heterocycloalkyl-Cl-4-alkyl, aryl, aryl-Cl-4-alkyl, heteroaryl, heteroaryl-Cl-4-alkyl, hydroxy or C1-4-alkyloxy and R10 denotes C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-Cl-4-alkyl, 5 heterocycloalkyl, heterocycloalkyl-Cl-4-alkyl, aryl, aryl-Cl-4-alkyl, heteroaryl or heteroaryl-Cl-4-alkyl, while the above-mentioned substituents must not be bound to a common carbon atom and heteroatoms must be separated from one another by at least two carbon atoms, and the aryl, heteroaryl, aryloxy and heteroaryloxy groups contained in the groups mentioned hereinbefore for Rd, Re as well as R1 to R5 may each be di- or trisubstituted independently of one another in the carbon skeleton by a group selected from among halogen, cyano, hydroxy, nitro, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-Cl-4-alkyl, C1-6-perchloroalkyl, C1-6-fluoroalkyl, perfluoroalkyl, C1-6-alkoxy, C1-6-fluoroalkoxy, C1-6-perfluoroalkoxy, C3-7-cyclo-alkyloxy, C3-7-cycloalkyl-Cl-4-alkyloxy, heterocycloalkyloxy, heterocycloalkyl-C1-4-alkyloxy C1-6-alkylsulphanyl, C3-7-cycloalkylsulphanyl, and a group selected from among R6R7N, R6R'N-CO, R6R7N-CO-NR8, R6R7N-SO, R6R7N-S02, R6R7N-S02-NR8, R9-CO, R9-CO-NR8, R10-SO, R10-SO-NR8, R10-S02, R10-SO2-NR 8- and R10-CO-O, while R6 to R10 are as hereinbefore defined.
The invention also relates to the tautomers, stereoisomers, mixtures and salts, particularly the physiologically acceptable salts, of the compounds according to the invention.
The compounds of general formula (I) according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, in particular they suppress the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1).
Therefore this invention also relates to the use of the compounds according to the invention, including the physiologically acceptable salts, as pharmaceutical compositions.
This invention further relates to pharmaceutical compositions containing at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.
A further object of this invention is the use of at least one compound according to the 1o invention or a physiologically acceptable salt of such a compound for preparing a pharmaceutical composition that is suitable for the treatment or prevention of diseases or conditions that can be influenced by suppressing the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1).
The invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition which is suitable for the treatment of metabolic disorders, for example type I or II diabetes mellitus.
The invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition for suppressing the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1).
A further object of this invention is a process for preparing a pharmaceutical composition according to the invention, characterised in that a compound according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
3o The present invention also relates to a process for preparing the compounds of general formula (I) according to the invention.
This invention further relates to pharmaceutical compositions containing at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.
A further object of this invention is the use of at least one compound according to the 1o invention or a physiologically acceptable salt of such a compound for preparing a pharmaceutical composition that is suitable for the treatment or prevention of diseases or conditions that can be influenced by suppressing the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1).
The invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition which is suitable for the treatment of metabolic disorders, for example type I or II diabetes mellitus.
The invention also relates to the use of at least one compound according to the invention for preparing a pharmaceutical composition for suppressing the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1).
A further object of this invention is a process for preparing a pharmaceutical composition according to the invention, characterised in that a compound according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
3o The present invention also relates to a process for preparing the compounds of general formula (I) according to the invention.
Detailed description of the invention Unless stated otherwise, the groups, radicals and substituents, particularly R, R1 to R4, X, Y, Z and A have the meanings given hereinbefore and hereinafter.
If groups, substituents or radicals occur more than once in a compound, they may have the same or different meanings.
Preferred compounds of the above general formula (I) are those wherein the bicyclic io heteroaromatic group Aj II (II) kA A
looo denotes naphthalene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, [1,5]naphthyridine, [1,8]naphthyridine, pyrido[3,2-d]pyrimidine, pyrimido[5,4-d]pyrimidine, or pteridine, and Ra to Rf, R1 to R10, A and Z are as hereinbefore defined, with the proviso that at least one of the groups Rd and Re denotes H, halogen or C1.3-alkyl.
Particularly preferred are those compounds of the above general formula (I), wherein the bicyclic heteroaromatic group Aj II (II) looo kA A eA
denotes naphthalene, quinoline, quinazoline, quinoxaline or cinnoline, Ra denotes H, a group of formula o-~
If groups, substituents or radicals occur more than once in a compound, they may have the same or different meanings.
Preferred compounds of the above general formula (I) are those wherein the bicyclic io heteroaromatic group Aj II (II) kA A
looo denotes naphthalene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, [1,5]naphthyridine, [1,8]naphthyridine, pyrido[3,2-d]pyrimidine, pyrimido[5,4-d]pyrimidine, or pteridine, and Ra to Rf, R1 to R10, A and Z are as hereinbefore defined, with the proviso that at least one of the groups Rd and Re denotes H, halogen or C1.3-alkyl.
Particularly preferred are those compounds of the above general formula (I), wherein the bicyclic heteroaromatic group Aj II (II) looo kA A eA
denotes naphthalene, quinoline, quinazoline, quinoxaline or cinnoline, Ra denotes H, a group of formula o-~
or a Cl_4-alkyl group, which may be substituted by Cl_4-alkoxy, hydroxy, di-(Cl_3-alkyl)-amino, pyrrolidin-1-yl, piperidin-1 -yl, morpholin-4-yl, piperazin-1 -yl or 4-methyl-piperazin-1 -yl, Rb and Rc independently of one another denote chlorine, bromine or C1_2-alkyl, Z denotes CH or N, Rd denotes H, halogen, cyano, hydroxy, nitro, C1_4-alkyl, C2.4-alkenyl, C2.4-alkynyl, aryl-C2.3-alkynyl, C1_4-fluoroalkyl, C1_4-perfluoroalkyl, C3.6-cycloalkyl, C3.6-cycloalkyl-C1_4-alkyl, heterocycloalkyl, heterocycloalkyl-C1_4-alkyl, aryl, aryl-C1_4-alkyl, heteroaryl, heteroaryl-C1_4-alkyl, C1_4-alkoxy, C1_4-fluoroalkoxy, Cl_4-perfluoroalkoxy, C3.6-cycloalkyloxy, C3.6-cycloalkyl-Cl_4-alkyloxy, heterocycloalkyloxy, heterocycloalkyl-Cl_4-alkoxy, aryloxy, aryl-Cl_4-alkyloxy, heteroaryloxy, heteroaryl-C1_4-alkyloxy, C1_4-alkylsulphanyl or C3.6-cyclo-alkylsulphanyl, while the aryl and heteroaryl groups contained in the groups mentioned hereinbefore for Rd may optionally be substituted by halogen, Cl_3-alkyl, trichloromethyl, phenyl, phenyl-C1_3-alkyl, hydroxy, C1_3-alkoxycarbonyl, phenyloxy-C1_3-alkyl, phenylsulphonyl-C1_3-alkyl, morpholin-4-yl-C1_3-alkyl, cyano, amino, C1_3-alkylamino, di-(C1_3-alkyl)-amino, amino-C1_3-alkylamino, C1_3-alkylamino-C1_3-alkylamino, di-(C1_3-alkyl)-amino-C1_3-alkylamino, N-(amino-C1_3-alkyl)-N-(C1_3-alkyl)-amino, N-(Cl_3-alkylamino-C1_3-alkyl)-N-(C1_3-alkyl)-amino, N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino, morpholin-4-yl, piperazin-1-yl or 4-(C1_3-al kyl)-piperazin-1-yl, or a group selected from among R'R2N, R'R2N-CO, R'R2N-CO-NR3, R' R2N-SO, R' R2N-S02, R' R2N-S02-NR3, R4-CO, R4-CO-NR3, R5-SO, R5- 35- 5- 3SO-NR, RS02- and RS02-NR, wherein R1 denotes H, C1_4-alkyl, hydroxy-C1_4-alkyl, C3.6-cycloalkyl, C3.6-cycloalky-C1_4-alkyl, heterocycloalkyl, heterocycloalkyl-C1_4-alkyl, aryl, aryl-C1_4-alkyl, heteroaryl or heteroaryl-C1_4-alkyl, R2 denotes H, C1-4-alkyl, hydroxy-Cl-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalky-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-Cl-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-Cl-4-alkyl, R3 denotes H, C1-4-alkyl, C3-6-cycloalkyl or C3-6-cycloalkyl-Cl-4-alkyl, R4 denotes C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-Cl-4-alkyl, heterocycloalkyl, aryl, aryl-Cl-4-alkyl, heteroaryl, heteroaryl-Cl-4-alkyl, hydroxy or C1-4-alkyloxy and R5 denotes C1-4-alkyl, C3-6-cycloalkyl, heterocycloalkyl, aryl, aryl-Cl-4-alkyl, heteroaryl or heteroaryl-Cl-4-alkyl, while the aryl and heteroaryl groups contained in the groups mentioned hereinbefore for R' to R5 may optionally be substituted by halogen, cyano, C1-3-alkoxy, C1-3-alkoxycarbonyl, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, morpholin-4-ylcarbo-nyl, piperazin-1-ylcarbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, amino-Cl-3-alkyl, amino-Cl-3-alkylamino, C1-3-alkylamino-Cl-3-alkyl-amino, di-(C1-3-alkyl)-amino-Cl-3-alkylamino, N-(amino-Cl-3-alkyl)-N-(C1-3-alkyl)-amino, N-(C1-3-alkylamino-Cl-3-alkyl)-N-(C1-3-alkyl)-amino or N-[di-(C1-3-alkyl)-amino-Cl-3-alkyl]-N-(C1-3-alkyl)-amino, Re has the meaning given hereinbefore for Rd, with the proviso that at least one of the groups Rd and Re must be H, halogen or C1-3-alkyl, and Rf denotes H or C1-3-alkyl.
Particularly preferred are those compounds of the above general formula (I), wherein the bicyclic heteroaromatic group of general formula (II) denotes naphthalene or quinoline, Ra denotes H or a C1_4-alkyl group optionally substituted by a di-(Cl_3-alkyl)-amino group, Rb and Rc independently of one another denote chlorine, bromine or C1_2-alkyl, Z denotes CH, Rd denotes H, or, if Re denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1_3-alkoxy, 5-methyl-[1,2,4]oxadiazolyl, aminocarbonyl, wherein a hydrogen atom may be replaced by a C1_3-alkyl group and the second hydrogen atom may be replaced independently thereof by a Cl_3-alkyl, phenyl or phenyl-Cl_3-alkyl group, and amino, wherein a hydrogen atom may be replaced by a C1_3-alkyl group and the second hydrogen atom may be replaced independently thereof by a C1_3-alkyl or a phenylsulphonyl group, Re denotes H, or, if Rd denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1_3-alkyl, C1_3-alkoxy, furanyl, oxazolyl, isoxazolyl, which may be substituted in each case by one or two C1_3-alkyl groups, [1,2,4]oxadiazolyl, which may be substituted by C1_3-alkyl, trichloromethyl, phenyl, benzyl, hydroxy, Cl_3-alkoxycarbonyl, phenyloxymethyl, phenyl-sulphonylmethyl or morpholin-4-ylmethyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, which may be substituted by C1_3-alkyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, which may be substituted in each case by Cl_3-alkyl, cyano, amino, Cl_3-alkylamino, di-(Cl_3-alkyl)-amino, di-(C1_3-alkyl)-amino-C1_3-alkylamino, N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino, morpholin-4-yl or piperazin-1-yl, pyrrolidin-1 -ylcarbonyl, 3,4-dihydro-1 H-isoquinolin-2-ylcarbonyl, and a group of formula n R'R2N-CO, R'R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1_3-alkyl, hydroxy-C1_3-alkyl, C3.6-cycloalkyl-C1_3-alkyl, phenyl, phenyl-Cl_3-alkyl, pyridinyl or pyridinyl-Cl_3-alkyl, R2 denotes H or C1_3-alkyl, R3 denotes H or C1_3-alkyl, and R4 denotes Cl_3-alkyl, phenyl, phenyl-Cl_3-alkyl, pyridinyl or pyridinyl-Cl_3-alkyl, while the phenyl and pyridinyl groups contained in R1 to R4 may optionally be substituted by chlorine, cyano, methoxy, carboxy, aminocarbonyl, Cl_3-alkylaminocarbonyl, di-(Cl_3-alkyl)-aminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, amino, C1 _3-alkylamino, di-(C1_3-alkyl)-amino, aminomethyl, di-(C1_3-alkyl)-amino-C1_3-alkylamino or N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino, and Rf denotes H or C1_3-alkyl.
Most particularly preferred are those compounds of the above general formula (I), wherein the bicyclic heteroaromatic group of formula (II) is naphthalene or quinoline, Ra denotes H, Rb and Rc independently of one another denote chlorine, bromine or methyl, Z denotes CH, Rd denotes H, or, if Re denotes H, it may also denote a group selected from among C1_2-alkoxy, 5-methyl-[1,2,4]oxadiazole, N-phenylsulphonyl-N-methyl-amino, N-methyl-N-phenyl-aminocarbonyl, N-benzyl-aminocarbonyl and N-benzyl-N-methyl-aminocarbonyl, Re denotes H, or, if Rd denotes H, it may also denote a group selected from among methoxy, furanyl, oxazolyl, isoxazolyl, 3,5-dimethyl-isoxazole, 3-methyl-[1,2,4]oxadiazolyl, 5-methyl-[1,2,4]oxadiazolyl, 5-trichloromethyl-[1,2,4]oxadia-zolyl, 5-isopropyl-[1,2,4]oxadiazolyl, 3-phenyl-[1,2,4]oxadiazolyl, 5-phenyl-[1,2,4]oxadiazolyl, 3-benzyl-[1,2,4]oxadiazolyl, 5-benzyl-[1,2,4]oxadiazolyl, 5-hydroxy-[1,2,4]oxadiazolyl, 3-ethoxycarbonyl-[1,2,4]oxadiazolyl, 3-phenyl-oxymethyl-[1,2,4]oxadiazolyl, 3-phenylsulphonylmethyl-[1,2,4]oxadiazolyl, 5-(morpholin-4-ylmethyl)-[1,2,4]oxadiazolyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazo-lyl, 4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, pyridinyl, pyrimidinyl, 4-(piperazin-1-yl)-pyrimidinyl, 2-(morpholin-4-yl)-pyrimidinyl, 4-(morpholin-4-yl)-pyrimidinyl, 4-(2-dimethylamino-ethylamino)-pyrimidinyl, 4-[N-(2-dimethylamino-ethyl)-N-methyl-amino]-pyrimidinyl, 5-(morpholin-4-yl)-pyrazin-2-yl, 5-(2-dimethyl amino-ethyl amino)-pyrazin-2-yl, 6-(morpholin-4-yl)-pyridazin-3-yl, 6-(2-dimethylamino-ethylamino)-pyridazin-3-yl, pyrrolidin-1 -ylcarbonyl, 3,4-dihydro-1 H-isoquinolin-2-ylcarbonyl, and a group of formula R'R2N-CO, R'R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1_3-alkyl, hydroxyethyl, cyclohexylmethyl, phenyl, benzyl, 2-phenyl-ethyl, pyridinyl or pyridinylmethyl, R2 denotes H or methyl, R3 denotes H
and R4 denotes phenyl, benzyl, 2-phenyl-ethyl or pyridinyl, while the phenyl, benzyl and 2-phenyl-ethyl groups contained in R1 and R4 may be substituted by a cyano, methoxy, carboxy, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1 -ylcarbonyl or aminomethyl group and the pyridinyl and pyridinylmethyl groups contained in R1 and R4 may be substituted by a chlorine atom or a 2-dimethylamino-ethylamino or N-(2-dimethylamino-ethyl)-N-(methyl)-amino group, and Rf denotes H, the enantiomers, the mixtures thereof and the salts thereof, but particularly the compounds of general formula Rd Re O
HO ~
N
O
O
Rb (Ia) Rc wherein Rb and Rc each denote chlorine, Rd denotes H, or, if Re denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1_3-alkyl, C1_3-alkoxy, 5-methyl-[1,2,4]oxadiazolyl, aminocarbonyl, wherein a hydrogen atom may be replaced by a C1_3-alkyl group and the second hydrogen atom may be replaced independently thereof by a Cl_3-alkyl, phenyl or phenyl-Cl_3-alkyl group, and amino, wherein a hydrogen atom may be replaced by a C1_3-alkyl group and the second hydrogen atom may be replaced independently thereof by a C1_3-alkyl or a phenylsulphonyl group, and Re denotes H, or, if Rd denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1_3-alkyl, C1_3-alkoxy, furanyl, oxazolyl, isoxazolyl, which may be substituted in each case by one or two C1_3-alkyl groups, [1,2,4]oxadiazolyl, which may be substituted by C1_3-alkyl, trichloromethyl, phenyl, benzyl, hydroxy, Cl_3-alkoxycarbonyl, phenyloxymethyl, phenyl-sulphonylmethyl or morpholin-4-ylmethyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, which may be substituted by C1_3-alkyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, which may be substituted in each case by Cl_3-alkyl, cyano, amino, Cl_3-alkylamino, di-(Cl_3-alkyl)-amino, di-(C1_3-alkyl)-amino-C1_3-alkylamino, N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino, morpholin-4-yl or piperazin-1-yl, 5 pyrrolidin-1 -ylcarbonyl, 3,4-dihydro-1 H-isoquinolin-2-ylcarbonyl, and a group of formula n R'R2N-CO, R'R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1_3-alkyl, hydroxy-C1_3-alkyl, C3.6-cycloalkyl-C1_3-alkyl, 10 phenyl, phenyl-Cl_3-alkyl, pyridinyl or pyridinyl-Cl_3-alkyl, R2 denotes H or C1_3-alkyl, R3 denotes H or C1_3-alkyl, and R4 denotes phenyl, phenyl-Cl_3-alkyl, pyridinyl or pyridinyl-Cl_3-alkyl, while the phenyl and pyridinyl groups contained in R1 to R4 may optionally be substituted by chlorine, cyano, methoxy, carboxy, aminocarbonyl, Cl_3-alkylaminocarbonyl, di-(Cl_3-alkyl)-aminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, amino, C1 _3-alkylamino, di-(C1_3-alkyl)-amino, aminomethyl, di-(C1_3-alkyl)-amino-C1_3-alkylamino or N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino.
The following compounds may be mentioned by way of example:
(1) [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (2) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid, (3) {(3,5-dichloro-phenylsulphonyl)-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid, (4) [(5-benzylaminocarbonyl-naphthalen-1 -yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (5) [(3,5-dichloro-phenylsulphonyl)-(5-pyrimidin-2-yl-naphthalen-1-yl)-amino]-acetic acid, (6) {(3,5-dichloro-phenylsulphonyl)-[5-(5-morpholin-4-ylmethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid, (7) ((3,5-d ichloro-phenylsulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid, (8) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-ureido)-naphthalen-1-yl]-amino}-acetic acid, (9) [[5-(3-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (10) [[5-(2-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenyl-sulphonyl)-amino]-acetic acid, (11) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(piperazin-1 -ylcarbonyl)-benzylamino-carbonyl]-naphthalen-1-yl}-amino)-acetic acid, (12) {(3,5-dichloro-phenylsulphonyl)-[5-(4-methylaminocarbonyl-benzylamino-carbonyl)-naphthalen-1-yl]-amino}-acetic acid, (13) {(3,5-dichloro-phenylsulphonyl)-[5-(3-methylaminocarbonyl-benzylamino-carbonyl)-naphthalen-1-yl]-amino}-acetic acid, (14) {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid, (15) ((3,5-dichloro-phenylsulphonyl)-{6-[5-(2-dimethyl amino-ethyl amino)-pyrazin-2-yl]-naphthalen-2-yl}-amino)-acetic acid, (16) {(3,5-dichloro-phenylsulphonyl)-[6-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetic acid, (17) [(3,5-dichloro-phenylsulphonyl)-quinolin-8-yl-amino]-acetic acid and (18) [(3,5-dichloro-phenylsulphonyl)-(6-methoxy-quinolin-8-yl)-amino]-acetic acid.
3o Terms and definitions used Some terms used hereinbefore and hereinafter to describe the compounds according to the invention are defined more specifically below.
Unless otherwise stated, all the substituents are independent of one another.
If for example there are a plurality of C1_6-alkyl groups as substituents in one group, in the case of three C1_6-alkyl substituents, independently of one another, one may represent methyl, one n-propyl and one tert-butyl.
Where a hyphen open on one side "-" is used in the structural formula of a substituent, this hyphen is to be understood as the linkage point to the remainder of the molecule. The substituent replaces the corresponding groups Ra, Rb, etc..
If no hyphen open on one side is used in the structural formula of a substituent, the linkage point to the remainder of the molecule is clear from the name or the structural io formula itself.
By the term "optionally substituted" is meant within the scope of the invention the above-mentioned group, optionally substituted by a lower-molecular group.
Examples of lower-molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds.
The subject-matter of this invention also includes the compounds according to the invention, including the salts thereof, wherein one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
The term "halogen" within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine, chlorine and bromine are regarded as preferred halogens.
By the term "C1_n-alkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to n carbon atoms. Examples include:
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, 3o etc.. Unless described otherwise, the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc..
By the term "C1_n-fluoroalkyl" (including those which are part of other groups) are meant partly fluorinated, branched and unbranched alkyl groups with 1 to n carbon atoms, in which at least one hydrogen atom is replaced by fluorine. Examples of such partly fluorinated alkyl groups include difluoromethyl, trifluoroethyl and tetrafluoroethyl.
By the term "C1_n-perfluoroalkyl" (including those which are part of other groups) is meant a F-(CF2)n group. Examples of such groups include trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-iso-propyl etc., but preferably trifluoromethyl and pentafluorethyl.
By the term "C2_n-alkenyl" (including those which are part of other groups) are meant branched and unbranched alkenyl groups, with 2 to n carbon atoms, which contain one or more double bonds. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless described otherwise, the definitions propenyl, butenyl, pentenyl and hexenyl include all the possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1 butenyl -, 2- butenyl, 3-butenyl, 1-methyl-1-propenyl and 1-methyl-propenyl etc..
By the term "C2_n-alkynyl" (including those which are part of other groups) are meant branched and unbranched alkynyl groups, with 2 to n carbon atoms, which contain one or more triple bonds. Examples include: ethynyl, propynyl or butynyl.
Unless described otherwise, the definitions propynyl and butynyl include all the possible isomeric forms of the groups in question. Thus, for example propynyl includes propynyl and 2-propynyl, butynyl includes 1- butynyl, 2- butynyl, 3-butynyl, 1-methyl-1-propynyl and 1-methyl-2-propynyl etc..
By the term "C3_n-cycloalkyl" (including those which are part of other groups) are meant saturated mono-, bi, tri or spirocyclic alkyl groups with 3 to n carbon atoms.
3o Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3,2,1]octyl, spiro[4,5]decyl, norpinyl, norbornyl, norcaryl, adamantyl.
Preferably the term C3_7-cycloalkyl includes monocyclic alkyl groups. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, hydroxy, methoxy, amino, methylamino and dimethylamino.
Particularly preferred are those compounds of the above general formula (I), wherein the bicyclic heteroaromatic group of general formula (II) denotes naphthalene or quinoline, Ra denotes H or a C1_4-alkyl group optionally substituted by a di-(Cl_3-alkyl)-amino group, Rb and Rc independently of one another denote chlorine, bromine or C1_2-alkyl, Z denotes CH, Rd denotes H, or, if Re denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1_3-alkoxy, 5-methyl-[1,2,4]oxadiazolyl, aminocarbonyl, wherein a hydrogen atom may be replaced by a C1_3-alkyl group and the second hydrogen atom may be replaced independently thereof by a Cl_3-alkyl, phenyl or phenyl-Cl_3-alkyl group, and amino, wherein a hydrogen atom may be replaced by a C1_3-alkyl group and the second hydrogen atom may be replaced independently thereof by a C1_3-alkyl or a phenylsulphonyl group, Re denotes H, or, if Rd denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1_3-alkyl, C1_3-alkoxy, furanyl, oxazolyl, isoxazolyl, which may be substituted in each case by one or two C1_3-alkyl groups, [1,2,4]oxadiazolyl, which may be substituted by C1_3-alkyl, trichloromethyl, phenyl, benzyl, hydroxy, Cl_3-alkoxycarbonyl, phenyloxymethyl, phenyl-sulphonylmethyl or morpholin-4-ylmethyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, which may be substituted by C1_3-alkyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, which may be substituted in each case by Cl_3-alkyl, cyano, amino, Cl_3-alkylamino, di-(Cl_3-alkyl)-amino, di-(C1_3-alkyl)-amino-C1_3-alkylamino, N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino, morpholin-4-yl or piperazin-1-yl, pyrrolidin-1 -ylcarbonyl, 3,4-dihydro-1 H-isoquinolin-2-ylcarbonyl, and a group of formula n R'R2N-CO, R'R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1_3-alkyl, hydroxy-C1_3-alkyl, C3.6-cycloalkyl-C1_3-alkyl, phenyl, phenyl-Cl_3-alkyl, pyridinyl or pyridinyl-Cl_3-alkyl, R2 denotes H or C1_3-alkyl, R3 denotes H or C1_3-alkyl, and R4 denotes Cl_3-alkyl, phenyl, phenyl-Cl_3-alkyl, pyridinyl or pyridinyl-Cl_3-alkyl, while the phenyl and pyridinyl groups contained in R1 to R4 may optionally be substituted by chlorine, cyano, methoxy, carboxy, aminocarbonyl, Cl_3-alkylaminocarbonyl, di-(Cl_3-alkyl)-aminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, amino, C1 _3-alkylamino, di-(C1_3-alkyl)-amino, aminomethyl, di-(C1_3-alkyl)-amino-C1_3-alkylamino or N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino, and Rf denotes H or C1_3-alkyl.
Most particularly preferred are those compounds of the above general formula (I), wherein the bicyclic heteroaromatic group of formula (II) is naphthalene or quinoline, Ra denotes H, Rb and Rc independently of one another denote chlorine, bromine or methyl, Z denotes CH, Rd denotes H, or, if Re denotes H, it may also denote a group selected from among C1_2-alkoxy, 5-methyl-[1,2,4]oxadiazole, N-phenylsulphonyl-N-methyl-amino, N-methyl-N-phenyl-aminocarbonyl, N-benzyl-aminocarbonyl and N-benzyl-N-methyl-aminocarbonyl, Re denotes H, or, if Rd denotes H, it may also denote a group selected from among methoxy, furanyl, oxazolyl, isoxazolyl, 3,5-dimethyl-isoxazole, 3-methyl-[1,2,4]oxadiazolyl, 5-methyl-[1,2,4]oxadiazolyl, 5-trichloromethyl-[1,2,4]oxadia-zolyl, 5-isopropyl-[1,2,4]oxadiazolyl, 3-phenyl-[1,2,4]oxadiazolyl, 5-phenyl-[1,2,4]oxadiazolyl, 3-benzyl-[1,2,4]oxadiazolyl, 5-benzyl-[1,2,4]oxadiazolyl, 5-hydroxy-[1,2,4]oxadiazolyl, 3-ethoxycarbonyl-[1,2,4]oxadiazolyl, 3-phenyl-oxymethyl-[1,2,4]oxadiazolyl, 3-phenylsulphonylmethyl-[1,2,4]oxadiazolyl, 5-(morpholin-4-ylmethyl)-[1,2,4]oxadiazolyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazo-lyl, 4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, pyridinyl, pyrimidinyl, 4-(piperazin-1-yl)-pyrimidinyl, 2-(morpholin-4-yl)-pyrimidinyl, 4-(morpholin-4-yl)-pyrimidinyl, 4-(2-dimethylamino-ethylamino)-pyrimidinyl, 4-[N-(2-dimethylamino-ethyl)-N-methyl-amino]-pyrimidinyl, 5-(morpholin-4-yl)-pyrazin-2-yl, 5-(2-dimethyl amino-ethyl amino)-pyrazin-2-yl, 6-(morpholin-4-yl)-pyridazin-3-yl, 6-(2-dimethylamino-ethylamino)-pyridazin-3-yl, pyrrolidin-1 -ylcarbonyl, 3,4-dihydro-1 H-isoquinolin-2-ylcarbonyl, and a group of formula R'R2N-CO, R'R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1_3-alkyl, hydroxyethyl, cyclohexylmethyl, phenyl, benzyl, 2-phenyl-ethyl, pyridinyl or pyridinylmethyl, R2 denotes H or methyl, R3 denotes H
and R4 denotes phenyl, benzyl, 2-phenyl-ethyl or pyridinyl, while the phenyl, benzyl and 2-phenyl-ethyl groups contained in R1 and R4 may be substituted by a cyano, methoxy, carboxy, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1 -ylcarbonyl or aminomethyl group and the pyridinyl and pyridinylmethyl groups contained in R1 and R4 may be substituted by a chlorine atom or a 2-dimethylamino-ethylamino or N-(2-dimethylamino-ethyl)-N-(methyl)-amino group, and Rf denotes H, the enantiomers, the mixtures thereof and the salts thereof, but particularly the compounds of general formula Rd Re O
HO ~
N
O
O
Rb (Ia) Rc wherein Rb and Rc each denote chlorine, Rd denotes H, or, if Re denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1_3-alkyl, C1_3-alkoxy, 5-methyl-[1,2,4]oxadiazolyl, aminocarbonyl, wherein a hydrogen atom may be replaced by a C1_3-alkyl group and the second hydrogen atom may be replaced independently thereof by a Cl_3-alkyl, phenyl or phenyl-Cl_3-alkyl group, and amino, wherein a hydrogen atom may be replaced by a C1_3-alkyl group and the second hydrogen atom may be replaced independently thereof by a C1_3-alkyl or a phenylsulphonyl group, and Re denotes H, or, if Rd denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1_3-alkyl, C1_3-alkoxy, furanyl, oxazolyl, isoxazolyl, which may be substituted in each case by one or two C1_3-alkyl groups, [1,2,4]oxadiazolyl, which may be substituted by C1_3-alkyl, trichloromethyl, phenyl, benzyl, hydroxy, Cl_3-alkoxycarbonyl, phenyloxymethyl, phenyl-sulphonylmethyl or morpholin-4-ylmethyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, which may be substituted by C1_3-alkyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, which may be substituted in each case by Cl_3-alkyl, cyano, amino, Cl_3-alkylamino, di-(Cl_3-alkyl)-amino, di-(C1_3-alkyl)-amino-C1_3-alkylamino, N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino, morpholin-4-yl or piperazin-1-yl, 5 pyrrolidin-1 -ylcarbonyl, 3,4-dihydro-1 H-isoquinolin-2-ylcarbonyl, and a group of formula n R'R2N-CO, R'R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1_3-alkyl, hydroxy-C1_3-alkyl, C3.6-cycloalkyl-C1_3-alkyl, 10 phenyl, phenyl-Cl_3-alkyl, pyridinyl or pyridinyl-Cl_3-alkyl, R2 denotes H or C1_3-alkyl, R3 denotes H or C1_3-alkyl, and R4 denotes phenyl, phenyl-Cl_3-alkyl, pyridinyl or pyridinyl-Cl_3-alkyl, while the phenyl and pyridinyl groups contained in R1 to R4 may optionally be substituted by chlorine, cyano, methoxy, carboxy, aminocarbonyl, Cl_3-alkylaminocarbonyl, di-(Cl_3-alkyl)-aminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, amino, C1 _3-alkylamino, di-(C1_3-alkyl)-amino, aminomethyl, di-(C1_3-alkyl)-amino-C1_3-alkylamino or N-[di-(C1_3-alkyl)-amino-C1_3-alkyl]-N-(C1_3-alkyl)-amino.
The following compounds may be mentioned by way of example:
(1) [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (2) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid, (3) {(3,5-dichloro-phenylsulphonyl)-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid, (4) [(5-benzylaminocarbonyl-naphthalen-1 -yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (5) [(3,5-dichloro-phenylsulphonyl)-(5-pyrimidin-2-yl-naphthalen-1-yl)-amino]-acetic acid, (6) {(3,5-dichloro-phenylsulphonyl)-[5-(5-morpholin-4-ylmethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid, (7) ((3,5-d ichloro-phenylsulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid, (8) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-ureido)-naphthalen-1-yl]-amino}-acetic acid, (9) [[5-(3-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (10) [[5-(2-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenyl-sulphonyl)-amino]-acetic acid, (11) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(piperazin-1 -ylcarbonyl)-benzylamino-carbonyl]-naphthalen-1-yl}-amino)-acetic acid, (12) {(3,5-dichloro-phenylsulphonyl)-[5-(4-methylaminocarbonyl-benzylamino-carbonyl)-naphthalen-1-yl]-amino}-acetic acid, (13) {(3,5-dichloro-phenylsulphonyl)-[5-(3-methylaminocarbonyl-benzylamino-carbonyl)-naphthalen-1-yl]-amino}-acetic acid, (14) {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid, (15) ((3,5-dichloro-phenylsulphonyl)-{6-[5-(2-dimethyl amino-ethyl amino)-pyrazin-2-yl]-naphthalen-2-yl}-amino)-acetic acid, (16) {(3,5-dichloro-phenylsulphonyl)-[6-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetic acid, (17) [(3,5-dichloro-phenylsulphonyl)-quinolin-8-yl-amino]-acetic acid and (18) [(3,5-dichloro-phenylsulphonyl)-(6-methoxy-quinolin-8-yl)-amino]-acetic acid.
3o Terms and definitions used Some terms used hereinbefore and hereinafter to describe the compounds according to the invention are defined more specifically below.
Unless otherwise stated, all the substituents are independent of one another.
If for example there are a plurality of C1_6-alkyl groups as substituents in one group, in the case of three C1_6-alkyl substituents, independently of one another, one may represent methyl, one n-propyl and one tert-butyl.
Where a hyphen open on one side "-" is used in the structural formula of a substituent, this hyphen is to be understood as the linkage point to the remainder of the molecule. The substituent replaces the corresponding groups Ra, Rb, etc..
If no hyphen open on one side is used in the structural formula of a substituent, the linkage point to the remainder of the molecule is clear from the name or the structural io formula itself.
By the term "optionally substituted" is meant within the scope of the invention the above-mentioned group, optionally substituted by a lower-molecular group.
Examples of lower-molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds.
The subject-matter of this invention also includes the compounds according to the invention, including the salts thereof, wherein one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
The term "halogen" within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine, chlorine and bromine are regarded as preferred halogens.
By the term "C1_n-alkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to n carbon atoms. Examples include:
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, 3o etc.. Unless described otherwise, the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc..
By the term "C1_n-fluoroalkyl" (including those which are part of other groups) are meant partly fluorinated, branched and unbranched alkyl groups with 1 to n carbon atoms, in which at least one hydrogen atom is replaced by fluorine. Examples of such partly fluorinated alkyl groups include difluoromethyl, trifluoroethyl and tetrafluoroethyl.
By the term "C1_n-perfluoroalkyl" (including those which are part of other groups) is meant a F-(CF2)n group. Examples of such groups include trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-iso-propyl etc., but preferably trifluoromethyl and pentafluorethyl.
By the term "C2_n-alkenyl" (including those which are part of other groups) are meant branched and unbranched alkenyl groups, with 2 to n carbon atoms, which contain one or more double bonds. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless described otherwise, the definitions propenyl, butenyl, pentenyl and hexenyl include all the possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1 butenyl -, 2- butenyl, 3-butenyl, 1-methyl-1-propenyl and 1-methyl-propenyl etc..
By the term "C2_n-alkynyl" (including those which are part of other groups) are meant branched and unbranched alkynyl groups, with 2 to n carbon atoms, which contain one or more triple bonds. Examples include: ethynyl, propynyl or butynyl.
Unless described otherwise, the definitions propynyl and butynyl include all the possible isomeric forms of the groups in question. Thus, for example propynyl includes propynyl and 2-propynyl, butynyl includes 1- butynyl, 2- butynyl, 3-butynyl, 1-methyl-1-propynyl and 1-methyl-2-propynyl etc..
By the term "C3_n-cycloalkyl" (including those which are part of other groups) are meant saturated mono-, bi, tri or spirocyclic alkyl groups with 3 to n carbon atoms.
3o Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3,2,1]octyl, spiro[4,5]decyl, norpinyl, norbornyl, norcaryl, adamantyl.
Preferably the term C3_7-cycloalkyl includes monocyclic alkyl groups. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, hydroxy, methoxy, amino, methylamino and dimethylamino.
By the term "aryl" (including those which are part of other groups) are meant aromatic ring systems with 6, 10 or 14 carbon atoms. Examples include: phenyl, naphthyl, anthracenyl or phenanthrenyl. Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, difluoromethyl, trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, amino, fluorine, chlorine, bromine and iodine.
Preferred aryl groups are naphthyl and phenyl, of which phenyl is particularly preferred.
By the term "heteroaryl" are meant 5- to 10-membered mono- or bicyclic aromatic heterocycles, wherein up to three carbon atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen and sulphur. Each of the above-mentioned heterocycles may optionally also be anellated to a benzene ring.
The ring may be linked to the molecule through a carbon atom or, if present, through a nitrogen atom.
The following are examples of five- or six-membered heterocyclic aromatic groups:
O Cl Ci NNO N CN /N N NN- N NNE N ~\-N
N~// O// I N. , CNJ L J N N N -N N N N N
The following are mentioned as examples of 5-1 0-membered bicyclic heteroaryl rings: pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, naphthyridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.
Unless otherwise stated, the heteroaromatic groups may be substituted by one or more groups selected from among methyl, ethyl, difluoromethyl, trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, amino, fluorine, chlorine, bromine and iodine.
Preferred heteroaryl groups are furanyl, thiophenyl, pyrrole, 1 H-imidazole, 1 H-pyrazole, oxazole, isoxazole, thiazole, [1,2,4]oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl and benzothiazolyl.
Particularly preferred heteroaryl groups are [1,2,4]oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.
By the term "heterocycloalkyl" are meant four- to seven-membered, preferably five- to six-membered, saturated heterocycles which contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, preferably oxygen and nitrogen.
5 The ring may be linked to the molecule via a carbon atom or, if present, via a nitrogen atom.
The following are mentioned by way of example:
HN HNo 00 So HNO O0 SO HN HN HOS
NH O HN HC HCO
~/ N H
io Unless otherwise mentioned, the heterocyclic group may be provided with one or more oxo groups. Examples include:
O O O O 0 H ^Y O
HN 0 O~ HNCNH O_ H S` vS=O H ~ li H O O N H
O HN
H N)~
v0 O
Unless otherwise mentioned, any nitrogen atoms contained in the ring may optionally 15 be substituted by a methyl, ethyl, acetyl or methylsulphonyl group and the cyclic carbon atoms may be substituted by a methyl, ethyl, hydroxy, methoxy, amino, methylamino or dimethylamino group.
Preferred heterocycloalkyl groups are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, piperazinyl, homopiperazinyl, 2-oxo-piperazinyl, 20 oxo-morpholinyl, 1,1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.
Particularly preferred heterocycloalkyl groups are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
The term enantiomerically pure describes within the scope of the present invention compounds of formula (I), which are present in an enantiomerical purity of at least 85%ee, preferably at least 90%ee, particularly preferably > 95%ee. The term ee (enantiomeric excess) is known in the art and describes the optical purity of chiral compounds.
Preferred aryl groups are naphthyl and phenyl, of which phenyl is particularly preferred.
By the term "heteroaryl" are meant 5- to 10-membered mono- or bicyclic aromatic heterocycles, wherein up to three carbon atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen and sulphur. Each of the above-mentioned heterocycles may optionally also be anellated to a benzene ring.
The ring may be linked to the molecule through a carbon atom or, if present, through a nitrogen atom.
The following are examples of five- or six-membered heterocyclic aromatic groups:
O Cl Ci NNO N CN /N N NN- N NNE N ~\-N
N~// O// I N. , CNJ L J N N N -N N N N N
The following are mentioned as examples of 5-1 0-membered bicyclic heteroaryl rings: pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, naphthyridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.
Unless otherwise stated, the heteroaromatic groups may be substituted by one or more groups selected from among methyl, ethyl, difluoromethyl, trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, amino, fluorine, chlorine, bromine and iodine.
Preferred heteroaryl groups are furanyl, thiophenyl, pyrrole, 1 H-imidazole, 1 H-pyrazole, oxazole, isoxazole, thiazole, [1,2,4]oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl and benzothiazolyl.
Particularly preferred heteroaryl groups are [1,2,4]oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.
By the term "heterocycloalkyl" are meant four- to seven-membered, preferably five- to six-membered, saturated heterocycles which contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, preferably oxygen and nitrogen.
5 The ring may be linked to the molecule via a carbon atom or, if present, via a nitrogen atom.
The following are mentioned by way of example:
HN HNo 00 So HNO O0 SO HN HN HOS
NH O HN HC HCO
~/ N H
io Unless otherwise mentioned, the heterocyclic group may be provided with one or more oxo groups. Examples include:
O O O O 0 H ^Y O
HN 0 O~ HNCNH O_ H S` vS=O H ~ li H O O N H
O HN
H N)~
v0 O
Unless otherwise mentioned, any nitrogen atoms contained in the ring may optionally 15 be substituted by a methyl, ethyl, acetyl or methylsulphonyl group and the cyclic carbon atoms may be substituted by a methyl, ethyl, hydroxy, methoxy, amino, methylamino or dimethylamino group.
Preferred heterocycloalkyl groups are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, piperazinyl, homopiperazinyl, 2-oxo-piperazinyl, 20 oxo-morpholinyl, 1,1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.
Particularly preferred heterocycloalkyl groups are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
The term enantiomerically pure describes within the scope of the present invention compounds of formula (I), which are present in an enantiomerical purity of at least 85%ee, preferably at least 90%ee, particularly preferably > 95%ee. The term ee (enantiomeric excess) is known in the art and describes the optical purity of chiral compounds.
The term "protective group" for the purposes of the present invention is to be understood as being a collective term for those organic groups with which certain functional groups of a molecule can be temporarily protected from attach by reagents, so that reactions can be carried out in a manner targeted on only the desired locations in the molecule. The protective groups should be capable of being introduced selectively under mild conditions and should be stable under the conditions of the planned reactions and cleaning operations, while racemisations and epimerisations should also be excluded. The protective groups should be cleavable 1o under mild conditions selectively and ideally in a high yield. The choice of a suitable protective group, suitable conditions for its introduction (solvent, temperature, duration, etc.) as well as the possible ways of removing the protective group are known in the art (e.g. P. Kocienski, Protecting Groups, 3rd ed. 2004, THIEME, Stuttgart, ISBN: 3131370033).
By an "organic solvent" is meant, within the scope of the invention, an organic, low-molecular substance which can dissolve other organic substances by a physical method. To be suitable the prerequisite for the solvent is that neither the dissolving substance nor the dissolved substance should be chemically altered during the dissolving process, i.e. the components of the solution should be recoverable in their original form by physical separation processes such as distillation, crystallisation, sublimation, evaporation or adsorption. For various reasons, not only the pure solvents but also mixtures that combine the dissolving properties may be used.
Examples include:
alcohols, preferably methanol, ethanol, propanol, butanol, octanol and cyclohexanol;
glycols, preferably ethyleneglycol and diethyleneglycol;
ethers / glycolethers, preferably diethyl ether, tert-butyl-methylether, dibutylether, anisol, dioxane, tetrahydrofuran, and mono-, di- and tri-, polyethyleneglycol ethers;
ketones, preferably acetone, butanone and cyclohexanone;
3o esters, preferably acetic acid esters and glycolesters;
amides and other nitrogen compounds, preferably dimethylformamide, pyridine, N-methylpyrrolidone and acetonitrile;
sulphur compounds, preferably carbon disulphide, dimethylsulphoxide and sulpholane;
nitro compounds, preferably nitrobenzene;
By an "organic solvent" is meant, within the scope of the invention, an organic, low-molecular substance which can dissolve other organic substances by a physical method. To be suitable the prerequisite for the solvent is that neither the dissolving substance nor the dissolved substance should be chemically altered during the dissolving process, i.e. the components of the solution should be recoverable in their original form by physical separation processes such as distillation, crystallisation, sublimation, evaporation or adsorption. For various reasons, not only the pure solvents but also mixtures that combine the dissolving properties may be used.
Examples include:
alcohols, preferably methanol, ethanol, propanol, butanol, octanol and cyclohexanol;
glycols, preferably ethyleneglycol and diethyleneglycol;
ethers / glycolethers, preferably diethyl ether, tert-butyl-methylether, dibutylether, anisol, dioxane, tetrahydrofuran, and mono-, di- and tri-, polyethyleneglycol ethers;
ketones, preferably acetone, butanone and cyclohexanone;
3o esters, preferably acetic acid esters and glycolesters;
amides and other nitrogen compounds, preferably dimethylformamide, pyridine, N-methylpyrrolidone and acetonitrile;
sulphur compounds, preferably carbon disulphide, dimethylsulphoxide and sulpholane;
nitro compounds, preferably nitrobenzene;
halogenated hydrocarbons, preferably dichloromethane, chloroform, tetrachlormethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane and chlorofluorocarbons;
aliphatic or alicyclic hydrocarbons, preferably benzines, petroleum ether, cyclohexane, methylcyclohexane, decaline and terpene-L.; and aromatic hydrocarbons, preferably benzene, toluene, o-xylene, m-xylene and p-xylene;
and corresponding mixtures thereof.
io Compounds of general formula (I) may contain acid groups, such as e.g.
carboxylic acid or phosphonic acid groups and/or basic groups such as e.g. amino functions.
Compounds of general formula (I) may therefore be present as internal salts, as salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine, inter alia. For preparing the alkali metal and alkaline earth metal salts of the compound of formula (I), it is preferable to use the alkali metal and alkaline earth metal hydroxides and hydrides, while the hydroxides and hydrides of the alkali metals, particularly sodium and potassium are preferred, and sodium and potassium hydroxide are particularly preferred. (See also Pharmaceutical Salts, S. M. Birge et al., J. Pharm. Sci. 1977, 66, 1-19) Methods of preparation The compounds according to the invention may be obtained using methods of synthesis that are known in principle. Preferably the compounds are obtained by methods of preparation according to the invention that are described more fully 3o hereinafter.
The preparation of compounds of general formula (I) may be carried out according to the process shown in Scheme 1 starting from a compound of general formula (III), wherein Ra, Rb, Rc, A and Z are as hereinbefore defined and Rd', Re' and Rf' either have the meanings given hereinbefore for Rd, Re and Rf or denote groups that can be converted into Rd, Re and Rf by known methods of synthesis.
Rd Re Rd e. R d' R e A\A A / A A/A R\ O \A A/ 11 11 ~W O~A/AI-A\A f A J~A \A Are \A
/A f HNA A Rf N R
S
H2N R -0 ~O
/ (I) (III) Rb O (IV) Rb O
Z Z
R
Scheme 1 Compounds of general formula (IV) are obtained by sulphonylation of compounds of general formula (III).
The sulphonylation is carried out with aromatic sulphonyl chlorides in the presence of io a base such as triethylamine, diisopropylethylamine, pyridine, or 4-dimethylamino-pyridine, but preferably pyridine. The reaction may be carried out in suitable solvents such as diethyl ether, tetrahydrofuran, toluene, pyridine, dichloromethane, or chloroform, but preferably dichloromethane. The temperature may be between 0 C
and 60 C, but preferably between 15 C and 40 C. Examples of reactions of this kind are described in Example II.
Compounds of general formula (I) are obtained from compounds of general formula (IV) by alkylation.
Suitable alkylating agents are acetic acid ester derivatives which contain in the 2-position a leaving group such as chlorine, bromine, iodine, p-tolylsuIphonate, methylsulphonate, or trifl uoromethyl suIphonate. The alkylation is carried out in a solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, and at a temperature between 0 C
and 100 C, but preferably between 15 C and 50 C.
Examples of reactions of this kind are described in Example I.
If acetic acid derivatives with a methyl or ethyl ester unit are used as alkylating 3o agents, the esters obtained may then be cleaved to form the free carboxylic acid.
aliphatic or alicyclic hydrocarbons, preferably benzines, petroleum ether, cyclohexane, methylcyclohexane, decaline and terpene-L.; and aromatic hydrocarbons, preferably benzene, toluene, o-xylene, m-xylene and p-xylene;
and corresponding mixtures thereof.
io Compounds of general formula (I) may contain acid groups, such as e.g.
carboxylic acid or phosphonic acid groups and/or basic groups such as e.g. amino functions.
Compounds of general formula (I) may therefore be present as internal salts, as salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine, inter alia. For preparing the alkali metal and alkaline earth metal salts of the compound of formula (I), it is preferable to use the alkali metal and alkaline earth metal hydroxides and hydrides, while the hydroxides and hydrides of the alkali metals, particularly sodium and potassium are preferred, and sodium and potassium hydroxide are particularly preferred. (See also Pharmaceutical Salts, S. M. Birge et al., J. Pharm. Sci. 1977, 66, 1-19) Methods of preparation The compounds according to the invention may be obtained using methods of synthesis that are known in principle. Preferably the compounds are obtained by methods of preparation according to the invention that are described more fully 3o hereinafter.
The preparation of compounds of general formula (I) may be carried out according to the process shown in Scheme 1 starting from a compound of general formula (III), wherein Ra, Rb, Rc, A and Z are as hereinbefore defined and Rd', Re' and Rf' either have the meanings given hereinbefore for Rd, Re and Rf or denote groups that can be converted into Rd, Re and Rf by known methods of synthesis.
Rd Re Rd e. R d' R e A\A A / A A/A R\ O \A A/ 11 11 ~W O~A/AI-A\A f A J~A \A Are \A
/A f HNA A Rf N R
S
H2N R -0 ~O
/ (I) (III) Rb O (IV) Rb O
Z Z
R
Scheme 1 Compounds of general formula (IV) are obtained by sulphonylation of compounds of general formula (III).
The sulphonylation is carried out with aromatic sulphonyl chlorides in the presence of io a base such as triethylamine, diisopropylethylamine, pyridine, or 4-dimethylamino-pyridine, but preferably pyridine. The reaction may be carried out in suitable solvents such as diethyl ether, tetrahydrofuran, toluene, pyridine, dichloromethane, or chloroform, but preferably dichloromethane. The temperature may be between 0 C
and 60 C, but preferably between 15 C and 40 C. Examples of reactions of this kind are described in Example II.
Compounds of general formula (I) are obtained from compounds of general formula (IV) by alkylation.
Suitable alkylating agents are acetic acid ester derivatives which contain in the 2-position a leaving group such as chlorine, bromine, iodine, p-tolylsuIphonate, methylsulphonate, or trifl uoromethyl suIphonate. The alkylation is carried out in a solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidone or dimethylsulphoxide, but preferably in dimethylformamide, in the presence of a base such as sodium carbonate, potassium carbonate or caesium carbonate, but preferably potassium carbonate, and at a temperature between 0 C
and 100 C, but preferably between 15 C and 50 C.
Examples of reactions of this kind are described in Example I.
If acetic acid derivatives with a methyl or ethyl ester unit are used as alkylating 3o agents, the esters obtained may then be cleaved to form the free carboxylic acid.
This may take place hydrolytically in an aqueous solvent, e.g. in water, methanol/water, isopropanol/water, acetic acid/water, tetra hyd rofu ra n/water or dioxane/water, but preferably in methanol/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, but preferably sodium hydroxide, or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 C, preferably at temperatures between 10 and 100 C. Examples of reactions of this kind are described in Examples 1 and 2.
If acetic acid derivatives with a tert.-butyl ester unit are used as alkylating agents, compounds of general formula (I) are obtained wherein Ra = tert.-butyl. The cleaving of the tert.-butyl group is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
Examples of reactions of this kind are described in Example 3.
Alternatively the intermediate compounds of general formula (IV) may also be prepared by the process shown in Scheme 2 according to the invention starting from a compound of general formula (V), wherein X denotes halogen or trifluoromethyl suIphonate.
HZN, Ss0 0 Rd' Re Rd Re Rd Re Rb A \A f/A
A\A A/ A\ \A A/ Z R (VII) 1 11 A q F
/'A \A\A F A A\RF Cu(OAc)2, NEt3 HN,O R
x R RO-B
b -(V) OR (VI) R O (IV) Z
R
Scheme 2 Compounds of general formula (V), wherein X denotes halogen, preferably bromine or iodine, are converted by metal-halogen exchange with a suitable reagent, e.g. n-butyllithium, tert.-butyllithium or phenylmagnesium bromide, intermediately into the corresponding organometallic compounds, which are then reacted with trialkylborates (cf. also Boronic Acids; Preparation and Applications in Organic Synthesis and Medicine, D. G. Hall ed., WILEY-VCH 2005, S. 28 fl). Examples of reactions of this kind are described in Example XXVI
Alternatively compounds of formula (V) wherein X is halogen or 5 trifluoromethyl suIphonate may be reacted with tetraa I koxyd i boron compounds (RO)2B-B(OR)2 or dialkoxyboranes HB(OR)2 in the presence of a suitable catalyst, for example PdC12(dppf), and a base to form the corresponding boron esters (VI) (see T. Ishiyama et al., J.Org. Chem. 1995, 60, 7508; M. Murata et al., J. Org.
Chem.
1997; 62, 6458; N. Miyaura et al., Tetrahedron Lett. 1997, 38, 3447; M. Murata et io al., J. Org. Chem. 2000; 65, 164).
After hydrolytic cleaving to obtain the free boric acid the boric acid esters (VI) thus obtained may then be reacted with sulphonamides of general formula (VII) to form the compounds of general formula (IV). This reaction is expediently carried out in the presence of copper(II)acetate and a tertiary amino base such as triethylamine or 15 pyridine in a suitable solvent such as tetrahydrofuran or dichloromethane (D. M. T.
Chan et al., Tetrahedron Lett. 1998, 39, 2933). Examples of reactions of this kind are described in Example XXIX.
The compounds of general formulae (III) to (VII) used as starting materials are known 20 from the literature in some cases or may be prepared using methods known from the literature or those described hereinbefore, optionally with the additional introduction of protective groups (see Examples I to XLI).
In the reactions described hereinbefore, any reactive groups present such as 25 carboxy, hydroxy, amino or alkylamino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a carboxy group may be a methyl, ethyl, tert.butyl or benzyl group.
For example, a protecting group for a hydroxy group may be an acetyl, benzyl or tetrahydropyranyl group.
Protecting groups for an amino or alkylamino may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
A methoxy- or ethoxycarbonyl unit is cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, but preferably in methanol/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, but preferably sodium hydroxide, or aprotically, e.g.
in the presence of iodotrimethylsilane, at temperatures between 0 and 120 C, preferably at io temperatures between 10 and 100 C.
A benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium on charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 100 C, but preferably at temperatures between 20 and 60 C, and under a hydrogen pressure of 1 to 7 bar, but preferably 1 to 3 bar.
However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.-butyl or tert.-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
Moreover, the compounds of general formula (I) obtained, or intermediate products from the synthesis of compounds of general formula (I), as already mentioned hereinbefore, may be resolved into their enantiomers and/or diastereomers.
Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one stereocentre may be resolved into their enantiomers.
Thus, for example, compounds of general formula (I), or intermediate products from the synthesis of compounds of general formula I, which occur as racemates may be separated by methods known per se (cf. N. L. Allinger and E. L. Eliel in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes.
If acetic acid derivatives with a tert.-butyl ester unit are used as alkylating agents, compounds of general formula (I) are obtained wherein Ra = tert.-butyl. The cleaving of the tert.-butyl group is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
Examples of reactions of this kind are described in Example 3.
Alternatively the intermediate compounds of general formula (IV) may also be prepared by the process shown in Scheme 2 according to the invention starting from a compound of general formula (V), wherein X denotes halogen or trifluoromethyl suIphonate.
HZN, Ss0 0 Rd' Re Rd Re Rd Re Rb A \A f/A
A\A A/ A\ \A A/ Z R (VII) 1 11 A q F
/'A \A\A F A A\RF Cu(OAc)2, NEt3 HN,O R
x R RO-B
b -(V) OR (VI) R O (IV) Z
R
Scheme 2 Compounds of general formula (V), wherein X denotes halogen, preferably bromine or iodine, are converted by metal-halogen exchange with a suitable reagent, e.g. n-butyllithium, tert.-butyllithium or phenylmagnesium bromide, intermediately into the corresponding organometallic compounds, which are then reacted with trialkylborates (cf. also Boronic Acids; Preparation and Applications in Organic Synthesis and Medicine, D. G. Hall ed., WILEY-VCH 2005, S. 28 fl). Examples of reactions of this kind are described in Example XXVI
Alternatively compounds of formula (V) wherein X is halogen or 5 trifluoromethyl suIphonate may be reacted with tetraa I koxyd i boron compounds (RO)2B-B(OR)2 or dialkoxyboranes HB(OR)2 in the presence of a suitable catalyst, for example PdC12(dppf), and a base to form the corresponding boron esters (VI) (see T. Ishiyama et al., J.Org. Chem. 1995, 60, 7508; M. Murata et al., J. Org.
Chem.
1997; 62, 6458; N. Miyaura et al., Tetrahedron Lett. 1997, 38, 3447; M. Murata et io al., J. Org. Chem. 2000; 65, 164).
After hydrolytic cleaving to obtain the free boric acid the boric acid esters (VI) thus obtained may then be reacted with sulphonamides of general formula (VII) to form the compounds of general formula (IV). This reaction is expediently carried out in the presence of copper(II)acetate and a tertiary amino base such as triethylamine or 15 pyridine in a suitable solvent such as tetrahydrofuran or dichloromethane (D. M. T.
Chan et al., Tetrahedron Lett. 1998, 39, 2933). Examples of reactions of this kind are described in Example XXIX.
The compounds of general formulae (III) to (VII) used as starting materials are known 20 from the literature in some cases or may be prepared using methods known from the literature or those described hereinbefore, optionally with the additional introduction of protective groups (see Examples I to XLI).
In the reactions described hereinbefore, any reactive groups present such as 25 carboxy, hydroxy, amino or alkylamino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a carboxy group may be a methyl, ethyl, tert.butyl or benzyl group.
For example, a protecting group for a hydroxy group may be an acetyl, benzyl or tetrahydropyranyl group.
Protecting groups for an amino or alkylamino may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
A methoxy- or ethoxycarbonyl unit is cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, methanol/water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, but preferably in methanol/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, but preferably sodium hydroxide, or aprotically, e.g.
in the presence of iodotrimethylsilane, at temperatures between 0 and 120 C, preferably at io temperatures between 10 and 100 C.
A benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium on charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 100 C, but preferably at temperatures between 20 and 60 C, and under a hydrogen pressure of 1 to 7 bar, but preferably 1 to 3 bar.
However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.-butyl or tert.-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
Moreover, the compounds of general formula (I) obtained, or intermediate products from the synthesis of compounds of general formula (I), as already mentioned hereinbefore, may be resolved into their enantiomers and/or diastereomers.
Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one stereocentre may be resolved into their enantiomers.
Thus, for example, compounds of general formula (I), or intermediate products from the synthesis of compounds of general formula I, which occur as racemates may be separated by methods known per se (cf. N. L. Allinger and E. L. Eliel in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes.
Compounds of general formula (I), or intermediate products from the synthesis of compounds of general formula (I), with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by chromatography on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active io substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Examples of optically active substances include optically active acids and the activated derivatives or optically active alcohols thereof.
Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-O-p-toluoyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula (I) obtained, or intermediate products from the synthesis of compounds of general formula I, may be converted into the salts thereof, for pharmaceutical use in particular into the physiologically acceptable salts thereof with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, the new compounds of general formula (I) obtained, or intermediate products from the synthesis of compounds of general formula I, if they contain a carboxy group, may, if desired, be converted into the salts thereof with inorganic or organic bases, for pharmaceutical use particularly into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Biological test The compounds of general formula (I) are inhibitors of the interaction between human liver glycogen phosphorylase (HLGP) and the protein PPP1 R3 (GL-subunit of glycogen-associated protein phosphatase 1 (PP1)). The effect of the compounds on the binding of the protein PPP1 R3 and the glycogen phosphorylase activated by phosphorylation is determined in a binding test based on SPA technology io (Amersham Pharmacia). The binding of the substances inhibits the interaction of the glycogen phosphorylase with the protein PPP1 R3B. PII measurements were made in triplicate in the 384-well format (Optiplate, Perkin Elmer). Human glycogen phosphorylase is recombinantly expressed in E. coli and purified. The isolated non-phosphorylated HLGP is radioactively labelled in a marking reaction with phosphorylase kinase (200-500 U/ mg, P2014, Sigma) and 33P-gamma ATP (110 TBq/ mmol, Hartmann Analytic) (Ref.: Cohen et al., Methods Enzymol. 1988, Vol pp 390). In a binding test, in a volume of 100 pl (test buffer: 50 mM Tris/HCI
pH 7.0, 0.1 mM EGTA, 0.1% mercaptoethanol), different amounts of a test substance (final concentration: 1 nM to 30 pM) are incubated at ambient temperature for 16 hours with 100000 cpm of labelled HLGP, 375 pg streptavidin-SPA Beads (RPNQ 0007, Amersham Pharmacia), 0.1 pg GL-peptide (Biotin-FPEWPSYLGYEKLGPYY). After centrifuging for 5 minutes at 500 g the plate is measured (Topcount, Packard).
The cpm values measured are used to calculate the IC50 values specified. The basal value is determined in the absence of the peptide and the maximum value is determined in the absence of the test substance.
The compounds of general formula (I) described in the Examples have IC50 values <
5 pM.
Indications In view of their ability to suppress the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1), the compounds of general formula (I) according to the invention and the corresponding pharma-ceutically acceptable salts thereof are theoretically suitable for treating and/or preventatively treating all those conditions or diseases that can be influenced by inhibiting the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1). Therefore the compounds according to the invention are particularly suitable for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, io atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia. These substances are also suitable for preventing beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta cells. The substances are also suitable for improving or restoring the functionality of pancreatic cells, and also for increasing the number and size of pancreatic beta cells. The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.
In particular, the compounds according to the invention, including the physiologically acceptable salts thereof, are suitable for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic complications.
The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide. Expediently, the dosage may be from 0.1 to 1000 mg, preferably 0.5 to 500 mg, by intravenous route, and 1 to 1000 mg, preferably 10 to 500 mg, by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula (I) prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcelIulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The compounds according to the invention may also be used in conjunction with 5 other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include in particular those which potentiate the therapeutic effect of an inhibitor of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1) according to the io invention with respect to one of the indications mentioned and/or which allow the dosage of an inhibitor of the interaction of glycogen phosphorylase a with the GL
subunit of glycogen-associated protein phosphatase 1 (PP1) according to the invention to be reduced. Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, 15 sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g.
KRP 297), alpha-glucosidase inhibitors (e.g. Miglitol, acarbose, voglibose), DPPIV
inhibitors (e.g. sitagliptine, vildagliptine), SGLT2-inhibitors, alpha2-antagonists, 20 insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. Other active substances suitable as combination partners are inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and 25 inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g.
bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors 30 such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or R3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. P-II antagonists or ACE inhibitors, ECE
inhibitors, diuretics, f3-blockers, Ca-antagonists, centrally acting anti hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-io 158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
A combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.
A combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein-kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes.
The dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
Therefore, in another aspect, this invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by inhibiting the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1). These are preferably metabolic diseases, particularly one of the diseases or conditions listed above, most particularly diabetes or diabetic complications.
The enantiomers are preferably separated by chromatography on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active io substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Examples of optically active substances include optically active acids and the activated derivatives or optically active alcohols thereof.
Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-O-p-toluoyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula (I) obtained, or intermediate products from the synthesis of compounds of general formula I, may be converted into the salts thereof, for pharmaceutical use in particular into the physiologically acceptable salts thereof with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, the new compounds of general formula (I) obtained, or intermediate products from the synthesis of compounds of general formula I, if they contain a carboxy group, may, if desired, be converted into the salts thereof with inorganic or organic bases, for pharmaceutical use particularly into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Biological test The compounds of general formula (I) are inhibitors of the interaction between human liver glycogen phosphorylase (HLGP) and the protein PPP1 R3 (GL-subunit of glycogen-associated protein phosphatase 1 (PP1)). The effect of the compounds on the binding of the protein PPP1 R3 and the glycogen phosphorylase activated by phosphorylation is determined in a binding test based on SPA technology io (Amersham Pharmacia). The binding of the substances inhibits the interaction of the glycogen phosphorylase with the protein PPP1 R3B. PII measurements were made in triplicate in the 384-well format (Optiplate, Perkin Elmer). Human glycogen phosphorylase is recombinantly expressed in E. coli and purified. The isolated non-phosphorylated HLGP is radioactively labelled in a marking reaction with phosphorylase kinase (200-500 U/ mg, P2014, Sigma) and 33P-gamma ATP (110 TBq/ mmol, Hartmann Analytic) (Ref.: Cohen et al., Methods Enzymol. 1988, Vol pp 390). In a binding test, in a volume of 100 pl (test buffer: 50 mM Tris/HCI
pH 7.0, 0.1 mM EGTA, 0.1% mercaptoethanol), different amounts of a test substance (final concentration: 1 nM to 30 pM) are incubated at ambient temperature for 16 hours with 100000 cpm of labelled HLGP, 375 pg streptavidin-SPA Beads (RPNQ 0007, Amersham Pharmacia), 0.1 pg GL-peptide (Biotin-FPEWPSYLGYEKLGPYY). After centrifuging for 5 minutes at 500 g the plate is measured (Topcount, Packard).
The cpm values measured are used to calculate the IC50 values specified. The basal value is determined in the absence of the peptide and the maximum value is determined in the absence of the test substance.
The compounds of general formula (I) described in the Examples have IC50 values <
5 pM.
Indications In view of their ability to suppress the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1), the compounds of general formula (I) according to the invention and the corresponding pharma-ceutically acceptable salts thereof are theoretically suitable for treating and/or preventatively treating all those conditions or diseases that can be influenced by inhibiting the interaction of glycogen phosphorylase a with the GL-subunit of glycogen-associated protein phosphatase 1 (PP1). Therefore the compounds according to the invention are particularly suitable for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, io atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia. These substances are also suitable for preventing beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta cells. The substances are also suitable for improving or restoring the functionality of pancreatic cells, and also for increasing the number and size of pancreatic beta cells. The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.
In particular, the compounds according to the invention, including the physiologically acceptable salts thereof, are suitable for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic complications.
The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide. Expediently, the dosage may be from 0.1 to 1000 mg, preferably 0.5 to 500 mg, by intravenous route, and 1 to 1000 mg, preferably 10 to 500 mg, by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula (I) prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcelIulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The compounds according to the invention may also be used in conjunction with 5 other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include in particular those which potentiate the therapeutic effect of an inhibitor of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1) according to the io invention with respect to one of the indications mentioned and/or which allow the dosage of an inhibitor of the interaction of glycogen phosphorylase a with the GL
subunit of glycogen-associated protein phosphatase 1 (PP1) according to the invention to be reduced. Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, 15 sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g.
KRP 297), alpha-glucosidase inhibitors (e.g. Miglitol, acarbose, voglibose), DPPIV
inhibitors (e.g. sitagliptine, vildagliptine), SGLT2-inhibitors, alpha2-antagonists, 20 insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. Other active substances suitable as combination partners are inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and 25 inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g.
bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors 30 such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or R3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. P-II antagonists or ACE inhibitors, ECE
inhibitors, diuretics, f3-blockers, Ca-antagonists, centrally acting anti hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-io 158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
A combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.
A combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein-kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes.
The dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
Therefore, in another aspect, this invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by inhibiting the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1). These are preferably metabolic diseases, particularly one of the diseases or conditions listed above, most particularly diabetes or diabetic complications.
The use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
Consequently, in another aspect, this invention relates to a pharmaceutical io composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
Thus, for example, a pharmaceutical composition according to the invention comprises a combination of a compound of formula (I) according to the invention or a physiologically acceptable salt of such a compound and at least one angiotensin II
receptor antagonist optionally together with one or more inert carriers and/or diluents.
The compound according to the invention, or one of the physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.
The Examples that follow are intended to illustrate the present invention without restricting it:
Consequently, in another aspect, this invention relates to a pharmaceutical io composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
Thus, for example, a pharmaceutical composition according to the invention comprises a combination of a compound of formula (I) according to the invention or a physiologically acceptable salt of such a compound and at least one angiotensin II
receptor antagonist optionally together with one or more inert carriers and/or diluents.
The compound according to the invention, or one of the physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.
The Examples that follow are intended to illustrate the present invention without restricting it:
Preparation of the starting compounds:
Example I
Methyl [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-2-yll-(3,5-dichloro-phenylsulphonyl)-aminol-acetate N
N
O
O TO
N I
O=s=0 CI I CI
A mixture of 3.00 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-cyano-benzylamide, 0.63 ml methyl bromoacetate and 1.80 g potassium carbonate in 50 ml N,N-dimethylformamide is combined with 50 io mg potassium iodide and stirred for 18 h at ambient temperature. Then another 50 pl methyl bromoacetate are added and the mixture is stirred for a further hour at ambient temperature. For working up 130 ml ice water are added. The precipitate formed is suction filtered, washed with water and dissolved in ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulphate and dried and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/ethyl acetate (90:10 to 85:15) as eluant.
Yield: 2.30 g (67 % of theory) Rf value: 0.50 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 582, 584, 586 [M+H]+
The following compounds are obtained analogously to Example I:
(1) methyl [[5-(benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenyl-suIphonyl)-amino]-acetate O H
I
O ~O
N
O=s=0 CI I CI
Rf value: 0.28 (silica gel, methylene chloride/methanol = 99:1) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(2) methyl [{5-[4-(tert.-butoxycarbonylamino-methyl)-benzylaminocarbonyl]-naphthalen-2-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetate O
H~O
O N~
O
N
O=s=0 CI I CI
Rf value: 0.54 (silica gel, methylene chloride/methanol = 95:5) io Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
(3) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-methylaminocarbonyl-naphthalen-2-yl)-amino]-acetate H
O N~
O O
N
O=s=0 Cl CI
Rf value: 0.60 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 523, 525, 527 [M+H]+
(4) benzyl 6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carboxylate ~I
x o o o o N
O=s=0 CI d CI
5 Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESI+): m/z = 617, 619, 621 [M+NH4]+
(5) tert. Butyl [(6-aminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate x O
0T, 0 I NHZ
N
O=s=0 ciJ Cl Rf value: 0.49 (silica gel, ethyl acetate/cyclohexane = 4:1) Mass spectrum (ESI+): m/z = 509, 511, 513 [M+H]+
(6) tert. Butyl [(6-cyano-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]- acetate /I N
N
O=s=0 CI d CI
Rf value: 0.80 (silica gel, cyclohexane/ethyl acetate = 3:1) (7) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(2-hydroxy-ethylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate y 0 0 N~~OH
N I ~ / H
O=S=0 CI I CI
Rf value: 0.45 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 551, 553, 555 [M-H]-(8 tert. Butyl) [(3,5-dichloro-phenylsulphonyl)-naphthalen-1-yl-amino]-acetate N` 1O CI
CI
Rf value: 0.80 (silica gel, cyclohexane/ethyl acetate = 3:1) io (9) tert. Butyl [(6-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate y O
00 \ \ N~
N I / H
O=S=0 CI I Cl (10) tert. Butyl [(5-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dimethyl-phenylsulphonyl)-amino]-acetate O H
O O
N
O=s=0 )c ~
Mass spectrum (ESI+): m/z = 559 [M+H]+
Rf value: 0.30 (silica gel, hexane/ethyl acetate = 1:1) (11) methyl [(3,5-dichloro-phenylsulphonyl)-(6-phenylaminocarbonyl-naphthalen-2-yl)-amino]-acetate I 0 ~
O O ~ N ~
N I / / H
O=s=0 CI I CI
Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(12) methyl [(3,5-dichloro-phenylsulphonyl)-(6-methylaminocarbonyl-naphthalen-2-yl)-amino]-acetate O O Ni N I / H
O=s=0 CI I d CI
Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 481, 483, 485 [M+H]+
(13) tert. Butyl [(6-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dimethyl-phenylsulphonyl)-amino]-acetate o OO N
H
O=s=0 Jtl' Rf value: 0.64 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 559 [M+H]+
(14) tert. Butyl [(7-benzoylamino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate NJ=N
0=s=0 H
CI I CI
Mass spectrum (ESI+): m/z = 585 [M+H]+
io (15) tert. Butyl [(7-amino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amminno]-acetate O
NH
N z o=s=O
CI Cl (16) tert. Butyl [(3,5-dichlorophenylsulphonyl)-(6-trifl uoromethanesuIphonyloxy-naphthalen-2-yl)-amino]-acetate O O.S0 F
O F F
N
O=s=0 CI J CI
Rf value: 0.90 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 648, 650, 652 [M+Cl]-(17) tert. Butyl [(7-cyano-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amminno]-acetate O
IN
O=s=0 CI d CI
Mass spectrum (ESI+): m/z = 508, 510, 512 [M+NH4]+
(18) tert. Butyl [(7-cyano-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N
Y II
O ~O ~
N I
O=s=0 Cl d CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 508, 510, 512 [M+NH4]+
(19) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O,N
O O C~
N
O=s=0 CI CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 548, 550, 552 [M+H]+
5 (20) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O-N~
x0 ~ N
N ~
O=s=0 ciJ CI
Mass spectrum (ESI+): m/z = 548, 550, 552 [M+H]+
io (21) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O O N
N
O=s=0 Cl 6 CI
Mass spectrum (ESI+): m/z = 610, 612, 614 [M+H]+
15 (22) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O
o N
Y O ~N
O O
O=s=0 CI d CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 606, 608, 610 [M+H]+
(23) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-naphthalen-2-yl]-amino}-acetate 0 coX>
N
0=s=0 CI Cl Mass spectrum (ESI+): m/z = 548, 550, 552 [M+H]+
io (24) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate N-O "1 N
Y N
O=s=0 CI CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(25) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyloxymethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O
N-C
\ / O ~" N
O ~O N~ Nz~
N
O=s=O
CI I CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 640, 642, 644 [M+H]+
(26) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenylsulphonylmethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O
N~S
O
O,N
O T0 N~
O=s=O
CI I CI
1o Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 688, 690, 692 [M+H]+
(27) methyl [(3,5-dichloro-phenylsulphonyl)-(4-methoxy-naphthalen-2-yl)-amino]-acetate o' I
O-'O
N
O=s=O
CI I CI
Rf value: 0.95 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 454, 456, 458 [M+H]+
(28) methyl [(5-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate H
O N
O cl O
cl Rf value: 0.82 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(29) methyl [(3,5-dichloro-phenylsulphonyl)-(5-methylaminocarbonyl-naphthalen-1-yl)-amino]-acetate H
O N", O
~N
O cl O
cl Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 481, 483, 485 [M+H]+
(30) tert. Butyl [(5-amino-naphthalen-1 -yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate NHZ
N O CI
O
CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 481, 483, 485 [M+H]+
(31) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylaminocarbonyl-naphthalen-1-yl)-amino]-acetate H
O cC
O
CI
Rf value: 0.36 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI-): m/z = 583, 585, 587 [M-H]-(32) tert. Butyl [(5-cyano-naphthalen-1 -yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N
II
N. '~ CI
S_q CI
Rf value: 0.46 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 508, 510, 512 [M+NH4]+
(32) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-pyrimidin-2-yl-naphthalen-yl)-amino]-acetate N~
N
O=S=0 Rf value: 0.68 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
5 (33) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-pyrimidin-2-yl-naphthalen-1-yl)-amino]-acetate N ~N
O
0 S / q CI
Rf value: 0.54 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(34) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylethyl-aminocarbonyl-naphthalen-1-yl)-amino]-acetate H
O~
)~"N, 1, CI
0 s CI
Rf value: 0.72 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 613, 615, 617 [M+H]+
Example I
Methyl [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-2-yll-(3,5-dichloro-phenylsulphonyl)-aminol-acetate N
N
O
O TO
N I
O=s=0 CI I CI
A mixture of 3.00 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-cyano-benzylamide, 0.63 ml methyl bromoacetate and 1.80 g potassium carbonate in 50 ml N,N-dimethylformamide is combined with 50 io mg potassium iodide and stirred for 18 h at ambient temperature. Then another 50 pl methyl bromoacetate are added and the mixture is stirred for a further hour at ambient temperature. For working up 130 ml ice water are added. The precipitate formed is suction filtered, washed with water and dissolved in ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulphate and dried and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/ethyl acetate (90:10 to 85:15) as eluant.
Yield: 2.30 g (67 % of theory) Rf value: 0.50 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 582, 584, 586 [M+H]+
The following compounds are obtained analogously to Example I:
(1) methyl [[5-(benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenyl-suIphonyl)-amino]-acetate O H
I
O ~O
N
O=s=0 CI I CI
Rf value: 0.28 (silica gel, methylene chloride/methanol = 99:1) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(2) methyl [{5-[4-(tert.-butoxycarbonylamino-methyl)-benzylaminocarbonyl]-naphthalen-2-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetate O
H~O
O N~
O
N
O=s=0 CI I CI
Rf value: 0.54 (silica gel, methylene chloride/methanol = 95:5) io Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
(3) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-methylaminocarbonyl-naphthalen-2-yl)-amino]-acetate H
O N~
O O
N
O=s=0 Cl CI
Rf value: 0.60 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 523, 525, 527 [M+H]+
(4) benzyl 6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carboxylate ~I
x o o o o N
O=s=0 CI d CI
5 Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESI+): m/z = 617, 619, 621 [M+NH4]+
(5) tert. Butyl [(6-aminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate x O
0T, 0 I NHZ
N
O=s=0 ciJ Cl Rf value: 0.49 (silica gel, ethyl acetate/cyclohexane = 4:1) Mass spectrum (ESI+): m/z = 509, 511, 513 [M+H]+
(6) tert. Butyl [(6-cyano-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]- acetate /I N
N
O=s=0 CI d CI
Rf value: 0.80 (silica gel, cyclohexane/ethyl acetate = 3:1) (7) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(2-hydroxy-ethylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate y 0 0 N~~OH
N I ~ / H
O=S=0 CI I CI
Rf value: 0.45 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 551, 553, 555 [M-H]-(8 tert. Butyl) [(3,5-dichloro-phenylsulphonyl)-naphthalen-1-yl-amino]-acetate N` 1O CI
CI
Rf value: 0.80 (silica gel, cyclohexane/ethyl acetate = 3:1) io (9) tert. Butyl [(6-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate y O
00 \ \ N~
N I / H
O=S=0 CI I Cl (10) tert. Butyl [(5-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dimethyl-phenylsulphonyl)-amino]-acetate O H
O O
N
O=s=0 )c ~
Mass spectrum (ESI+): m/z = 559 [M+H]+
Rf value: 0.30 (silica gel, hexane/ethyl acetate = 1:1) (11) methyl [(3,5-dichloro-phenylsulphonyl)-(6-phenylaminocarbonyl-naphthalen-2-yl)-amino]-acetate I 0 ~
O O ~ N ~
N I / / H
O=s=0 CI I CI
Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(12) methyl [(3,5-dichloro-phenylsulphonyl)-(6-methylaminocarbonyl-naphthalen-2-yl)-amino]-acetate O O Ni N I / H
O=s=0 CI I d CI
Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 481, 483, 485 [M+H]+
(13) tert. Butyl [(6-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dimethyl-phenylsulphonyl)-amino]-acetate o OO N
H
O=s=0 Jtl' Rf value: 0.64 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 559 [M+H]+
(14) tert. Butyl [(7-benzoylamino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate NJ=N
0=s=0 H
CI I CI
Mass spectrum (ESI+): m/z = 585 [M+H]+
io (15) tert. Butyl [(7-amino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amminno]-acetate O
NH
N z o=s=O
CI Cl (16) tert. Butyl [(3,5-dichlorophenylsulphonyl)-(6-trifl uoromethanesuIphonyloxy-naphthalen-2-yl)-amino]-acetate O O.S0 F
O F F
N
O=s=0 CI J CI
Rf value: 0.90 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 648, 650, 652 [M+Cl]-(17) tert. Butyl [(7-cyano-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amminno]-acetate O
IN
O=s=0 CI d CI
Mass spectrum (ESI+): m/z = 508, 510, 512 [M+NH4]+
(18) tert. Butyl [(7-cyano-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N
Y II
O ~O ~
N I
O=s=0 Cl d CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 508, 510, 512 [M+NH4]+
(19) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O,N
O O C~
N
O=s=0 CI CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 548, 550, 552 [M+H]+
5 (20) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O-N~
x0 ~ N
N ~
O=s=0 ciJ CI
Mass spectrum (ESI+): m/z = 548, 550, 552 [M+H]+
io (21) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O O N
N
O=s=0 Cl 6 CI
Mass spectrum (ESI+): m/z = 610, 612, 614 [M+H]+
15 (22) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O
o N
Y O ~N
O O
O=s=0 CI d CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 606, 608, 610 [M+H]+
(23) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,3,4]oxadiazol-2-yl)-naphthalen-2-yl]-amino}-acetate 0 coX>
N
0=s=0 CI Cl Mass spectrum (ESI+): m/z = 548, 550, 552 [M+H]+
io (24) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate N-O "1 N
Y N
O=s=0 CI CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(25) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyloxymethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O
N-C
\ / O ~" N
O ~O N~ Nz~
N
O=s=O
CI I CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 640, 642, 644 [M+H]+
(26) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenylsulphonylmethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate O
N~S
O
O,N
O T0 N~
O=s=O
CI I CI
1o Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 688, 690, 692 [M+H]+
(27) methyl [(3,5-dichloro-phenylsulphonyl)-(4-methoxy-naphthalen-2-yl)-amino]-acetate o' I
O-'O
N
O=s=O
CI I CI
Rf value: 0.95 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 454, 456, 458 [M+H]+
(28) methyl [(5-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate H
O N
O cl O
cl Rf value: 0.82 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(29) methyl [(3,5-dichloro-phenylsulphonyl)-(5-methylaminocarbonyl-naphthalen-1-yl)-amino]-acetate H
O N", O
~N
O cl O
cl Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 481, 483, 485 [M+H]+
(30) tert. Butyl [(5-amino-naphthalen-1 -yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate NHZ
N O CI
O
CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 481, 483, 485 [M+H]+
(31) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylaminocarbonyl-naphthalen-1-yl)-amino]-acetate H
O cC
O
CI
Rf value: 0.36 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI-): m/z = 583, 585, 587 [M-H]-(32) tert. Butyl [(5-cyano-naphthalen-1 -yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N
II
N. '~ CI
S_q CI
Rf value: 0.46 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 508, 510, 512 [M+NH4]+
(32) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-pyrimidin-2-yl-naphthalen-yl)-amino]-acetate N~
N
O=S=0 Rf value: 0.68 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
5 (33) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-pyrimidin-2-yl-naphthalen-1-yl)-amino]-acetate N ~N
O
0 S / q CI
Rf value: 0.54 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(34) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylethyl-aminocarbonyl-naphthalen-1-yl)-amino]-acetate H
O~
)~"N, 1, CI
0 s CI
Rf value: 0.72 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 613, 615, 617 [M+H]+
(35) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-methoxy-naphthalen-1 -yl)-amino]-acetate ~o ~
KIN- ~~ YCI
O OS
CI
Rf value: 0.46 (silica gel, cyclohexane/ethyl acetate = 4:1) 5 (36) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate 00 I N 0~
N
O=s=0 CI I CI
Rf value: 0.80 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 606, 608, 610 [M+H]+
(37) tert. Butyl {[6-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino}-acetate Y O-N
N
O=s=0 CI I CI
Rf value: 0.86 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(38) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenyloxymethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate Y O-N~
OO N
O
N
O=s=0 CI I CI
Rf value: 0.82 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 640, 642, 644 [M+H]+
(39) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenylsulphonylmethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate Y O-N
O DNS S.'O
N O
I /
o=s=o CI I / CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 688, 690, 692 [M+H]+
(40) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetate N-O
N
O
O ci OS
CI
(41) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-4-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetate N
H
O N
O~N. 'O cl ,S
O
:;f cl Rf value: 0.30 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(42) (66) tert. Butyl [[5-(cyclohexylmethyl-aminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate H
O N
O
O~N. 'O cl ,S
O
:;f cl Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate/acetic acid =
70:30:0.1) io Mass spectrum (ESI+): m/z = 605, 607, 609 [M+H]+
(43) tert. Butyl ((3,5-dichloro-phenylsuIphonyl)-{5-[(pyridin-2-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetate H
O N
n-N
O~N. 'O cl ,S
O
:;f cl Rf value: 0.52 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(44) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetate H
O N N
I
O
Oit",. 'O cl ,S
O :;f cl Rf value: 0.37 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(45) tert. Butyl [(3,5-dibromo-phenylsulphonyl)-(naphthalen-1-yl)-amino]-io acetate c O
O)_"' N Br OS / I
Br Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 571, 573, 575 [M+NH4]+
(46) tert. Butyl [(3-bromo-5-methyl-phenylsulphonyl)-(naphthalen-1 -yl)-amino]-acetate O
llu~N` , O O
OS -C;), Br Rf value: 0.68 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 507, 509 [M+NH4]+
(47) tert. Butyl [(3-bromo-5-chloro-phenylsulphonyl)-(naphthalen-1 -yl)-amino]-acetate CI
OS /
Br Rf value: 0.74 (silica gel, petroleum ether/ethyl acetate = 7:3) 5 Mass spectrum (ESI+): m/z = 527, 529, 531 [M+NH4]+
(48 tert. Butyl) [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N
H
O N
I
O
N` 1O CI
O OS / I
CI
1o Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(49) tert. Butyl [[5-(3-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate O N
N
O
O~N. '~ CI
S / I
CI
Rf value: 0.53 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(50) tert. Butyl [[5-(2-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate H
O N
N
Oit", N` 1O 0 CI
,S
O :;f CI
Rf value: 0.63 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 622, 624, 626 [M-H]-io (51) tert. Butyl [(2-cyano-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N N `gO 10 CYcl O
O O
CI
Rf value: 0.38 (silica gel, petroleum ether/ethyl acetate = 5:1) (52) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetate H
O~
I
Oit", N. 'O 0 CI
,S
O :;f CI
Rf value: 0.77 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(53) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetate /I
H N
O
O~N. 'O CI
,S /
O
CI
Rf value: 0.74 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
io (54) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetate O~
H
O N
II N \ 0 CI
s ' 1::
CI
Rf value: 0.68 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(55) tert. Butyl [[3-(phenylsulphonyl-methyl-amino)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate o=s=o N
YCI
o OS
CI
Mass spectrum (ESI+): m/z = 652, 654, 656 [M+NH4]+
(56) N-(4-amino-naphthalen-2-yl)-N-methyl-phenylsulphonamide o=s=o N
(57) tert. Butyl [(4-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate H
O N
O~N. '~ CI
S/ I
CI
io Mass spectrum (ESI+): m/z = 599, 601, 603 [M+H]+
(58) tert. Butyl [[5-(3-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate O N O
NHZ
O~N` '~ CI
S/
CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 642, 644, 646 [M+H]+
5 (59) tert. Butyl ((3,5-dichloro-phensulphonyl)-{5-[(pyridin-4-ylmethyl)-am inocarbonyl]-naphthalen-2-yl}-amino)-acetate "N
O N ~~
OO
N
o=s=o ciJ CI
Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
io (60) tert. Butyl ((3,5-dichloro-phensulphonyl)-{5-[(pyridin-3-ylmethyl)-am inocarbonyl]-naphthalen-2-yl}-amino)-acetate H
O N
OO
N
o=s=o ciJ Cl Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
15 (61) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[4-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetate N O
O
O~N` ~ CI
CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 712, 714, 716 [M+H]+
5 (62) tert. Butyl [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate H NHZ
O N
O
O~N` g ~ CI
O
CI
Rf value: 0.48 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 642, 644, 646 [M+H]+
(63) tert.-butyl 4-{4-[({6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate Fi 0 O
~N
0=s=0 ciJ CI
Mass spectrum (ESI+): m/z = 811, 813, 815 [M+H]+
(64) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[4-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-2-yl}-amino)-acetate O
N
H I
O
O
N
0=s=0 ciJ Cl Mass spectrum (ESI+): m/z = 712, 714, 716 [M+H]+
(65) tert.-butyl 4-{4-[({5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-io phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate O ON
H O N 'f 0-~
O
O
~ CI
CI
Rf value: 0.75 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 811, 813, 815 [M+H]+
(66) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[3-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetate O N O
1 CN) O
O~N` '~ CI S-q O
CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 729, 731, 733 [M+NH4]+
(67) tert.-butyl 4-{3-[({5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-1o phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate O N O
CN ~
N
O
, CI 0 0 /I\~ N` 1S'q O
CI
Rf value: 0.73 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 828, 830, 832 [M+NH4]+
(68) tert.-butyl 4-{2-[({6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate N /
O N
N O
N
O=s=0 0 ciJ CI
Mass spectrum (ESI+): m/z = 811, 813, 815 [M+H]+
(69) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[2-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetate N
O N
O
O
O~N. '~ CI
S/
CI
Rf value: 0.32 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 712, 714, 716 [M+H]+
io (70) tert.-butyl 4-{2-[({5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate N
O N
O N
0 ~NUO\/
~N,~
OS
CI
Rf value: 0.56 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 811, 813, 815 [M+H]+
(71) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetate H
O N N
I
O~N. 'O CI
S
O
CI
Rf value: 0.42 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 670, 672, 674 [M+H]+
(72) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetate N
O N
O"U~ N CI
CI
Rf value: 0.58 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 670, 672, 674 [M+H]+
(73) tert. Butyl {[5-(2-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino}-acetate H
O N
O NHZ
O
ON. 0 CI
O
CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 642, 644, 646 [M+H]+
5 (74) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-methylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetate O"U~ N` cI1cI
CI
Rf value: 0.33 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(75) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-methylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetate H H
O N N
I
O~N. 'O 0 CI
O
CI
Rf value: 0.33 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(76) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate N
O N
O O
N
O=s=0 ciJ CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 687, 689, 691 [M+NH4]+
(77) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-dimethylaminocarbonyl-io benzylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate H
0 N ~ NII
N
O=s=0 CI
CI
Rf value: 0.45 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 687, 689, 691 [M+NH4]+
(78) tert. Butyl [[3-(N-benzyl-N-methyl-aminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate :N
NIs CI
O ,S
O
CI
Rf value: 0.48 (silica gel, cyclohexane/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+NH4]+
(79) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-[3-(N-methyl-N-phenyl-aminocarbonyl)-naphthalen-1-yl]-acetate N
/ CI
O OS
CI
Rf value: 0.67 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 616, 618, 620 [M+NH4]+
(80) benzyl 5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carboxylate o Oit", N. 'O 0 CI
,S
O :;f CI
Rf value: 0.95 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 617, 619, 621 [M+NH4]+
(81) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-trifluoromethanesulphonyloxy-naphthalen-1-yl)-amino]-acetate F
O -SF
O" F
O
~N 1O CI
yo OS /
CI
Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 631, 633, 635 [M+NH4]+
(82) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-quinolin-8-yl-amino]-acetate O n-NN
KI N` 10 , CI
S/
CI
Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate = 4:1) Mass spectrum (ESI+): m/z = 467, 469, 471 [M+H]+
(83) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-methoxy-quinolin-8-yl)-amino]-acetate I
O ccI
)1_1 N, CI
S/
CI
Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 497, 499, 501 [M+H]+
Example II
6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-cyano-benzylamide N
N
O
HN
O=s=0 CI I CI
2.21 g 3,5-dichlorophenylsulphonyl chloride are added to a solution of 2.50 g 6-amino-naphthalene-1-carboxylic acid-4-cyano-benzylamide dissolved in 40 ml of pyridine while cooling with an ice bath. After one hour the ice bath is removed and the reaction mixture is stirred for another two hours at ambient temperature. Then the pyridine is distilled off in vacuo, the flask residue is io taken up in methylene chloride, washed with 2N hydrochloric acid and water, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/ethyl acetate (9:1 to 8:2) as eluant.
Yield: 3.53 g (83 % of theory) Rf value: 0.31 (silica gel, methylene chloride/ethyl acetate = 9:1) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
The following compounds are obtained analogously to Example II:
(1) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-benzylamide O H
HN
O=s=0 CI I Cl Rf value: 0.53 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 485, 487, 489 [M+H]+
(2) tert. Butyl [4-({[6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-5 carbonyl]-amino}-methyl)-benzyl]-carbamate O
H~0 O N~
HN
O=s=0 CI I CI
Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 612, 614, 616 [M-H]-10 (3) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-methylamide H
O N~
HN
O=s=0 CI Cl Rf value: 0.65 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 407, 409, 411 [M-H]-(4) benzyl 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylate O O
HN
O=s=O
CI I d CI
Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate = 1:1) (5) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid icn-11 OH
HN
O=s=O
CI I CI
Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-(6) 3,5-dichloro-N-naphthalen-1-yl-phenylsulphonamide HN, 1, ci O /I
CI
Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESI-): m/z = 350, 352, 354 [M-H]-(7) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-benzylamide O
N
H
HN
O=s=0 CI I d CI
Rf value: 0.77 (silica gel, hexane/ethyl acetate = 1:2) (8) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid O OH
HN
O=s=0 CI CI
Rf value: 0.45 (silica gel, methylene chloride/methanol = 9:1) (9) 6-(3,5-dimethyl-phenylsulphonylamino)-naphthalene-1-carboxylic acid-benzylamide O N
HN
O=s=0 Rf value: 0.27 (silica gel, hexane/ethyl acetate = 1:1) (10) 6-(3,5-dimethyl-phenylsulphonylamino)-naphthalene-2-carboxylic acid-benzylamide Jcn--~ OH
HN
O=s=O
Jtl' Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 356 [M+H]+
(11) N-(7-amino-naphthalen-2-yl)-3,5-dichloro-phenylsulphonamide H N = NHZ
O=s=0 CI CI
Mass spectrum (ESI-): m/z = 365, 367, 369 [M-H]-(12) 3,5-dichloro-N-(6-hydroxy-naphthalen-2-yl)-phenylsulphonamide OH
HN
O=s=O
ciJ CI
Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 368, 370, 372 [M+H]+
(13) methyl 7-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylate HN-'~ O
O=s=O 0~
CI CI
Mass spectrum (ESI+): m/z = 410, 412, 414 [M+H]+
(14) 3,5-dichloro-N-(4-methoxy-naphthalen-2-yl)-phenylsulphonamide O' HN
O=s=O
CI I CI
Rf value: 0.80 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 382, 384, 386 [M+H]+
(15) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid O OH
I
HN,S ci CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-(16) N-(5-amino-naphthalen-1-yl)-3,5-dichloro-phenylsulphonamide NHZ
I
HN,S ci CI
Rf value: 0.34 (silica gel, petroleum ether/ethyl acetate = 2:1) (17) 3,5-dichloro-N-(6-pyrimidin-2-yl-naphthalen-2-yl)-phenylsulphonamide N
HN \ \ N
/ /
O=s=0 ciJ CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 430, 432, 434 [M+H]+
5 (18) 3,5-dichloro-N-(5-pyrimidin-2-yl-naphthalen-1-yl)-phenylsulphonamide n N XN
HN, 1, ci /I
CI
Rf value: 0.20 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 430, 432, 434 [M+H]+
io (17) (3,5-dichloro-N-(6-methoxy-naphthalen-1 -yl)-phenylsulphonamide HN,0 Cl CI
Rf value: 0.26 (silica gel, cyclohexane/ethyl acetate = 4:1) Mass spectrum (ESI+): m/z = 382, 384, 386 [M+H]+
15 (18) 3,5-dibromo-N-naphthalen-1-yl-phenylsulphonamide '0 HN, Br Br Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 3:2) Mass spectrum (ESI-): m/z = 438, 440, 442 [M-H]-(19) 3-bromo-5-methyl-N-naphthalen-1-yl-phenylsulphonamide HN11, /I
Br Rf value: 0.69 (silica gel, petroleum ether/ethyl acetate = 3:2) Mass spectrum (ESI-): m/z = 374, 376 [M-H]-io (19) 3-bromo-5-chloro-N-naphthalen-1 -yl-phenylsulphonamide HN, 1, CI
/I
O
Br Rf value: 0.76 (silica gel, petroleum ether/ethyl acetate = 3:2) Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-(29) 3,5-dichloro-N-(2-cyano-naphthalen-1-yl)-phenylsulphonamide HN`S1 ~ifcI
CI
(30) N-[3-(phenylsulphonyl-methyl-amino)-naphthalen-1-yl]-3,5-dichloro-phenylsulphonamide I~
O=s=O
N
HN,S,, cI
O
CI
Mass spectrum (ESI-): m/z = 519, 521, 523 [M-H]-(31) 4-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid O OH
I
HN,0 CI
O
CI
Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-(32) 4-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid OH
O
HN,9, cI
O
CI
Mass spectrum (ESI+): m/z = 413 [M+NH4]+
(33) 3,5-dichloro-N-(5-hydroxy-naphthalen-1-yl)-phenylsulphonamide OH
HN,0 CI
CI
Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI-): m/z = 366, 368, 370 [M-H]-(34) 3,5-dichloro-N-quinolin-8-yl-phenylsulphonamide O
CI \ S-NH
I / o CI
Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 353, 355, 357 [M+H]+
(35) [(3,5-dichloro-N-(6-methoxy-quinolin-8-yl)-phenylsulphonamide ccI
H
NCI
CI
Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 383, 385, 387 [M+H]+
Example III
6-amino-naphthalene-1-carboxylic acid-benzylamide H
N
1.49 g 1-hydroxybenzotriazole, 3.53 g O-(benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium-tetrafluoroborate, 6.93 ml triethylamine and 1.20 ml benzylamine are added under an argon atmosphere to 1.87 g 6-aminonaphthoic acid in a mixture of 20 ml of tetrahydrofuran and 20 ml N,N-dimethylformamide. The light brown solution is stirred for 3 h at ambient io temperature. Then the solvent is distilled off using the rotary evaporator, the flask residue is slowly combined with ice water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with 2N citric acid and saturated sodium chloride solution. A precipitate is formed which is suction filtered, washed with water and ethyl acetate and dried. The filtrate is combined with a little methanol, the organic phase is separated off, dried on magnesium sulphate and evaporated down. The flask residue is combined with the suction filtered precipitate, stirred with ethyl acetate, suction filtered, washed with some ethyl acetate and diethyl ether and dried in the desiccator.
Yield: 1.81 g (66 % of theory) Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 277 [M+H]+
The following compounds are obtained analogously to Example III:
(1) tert. Butyl (4-{[(6-amino-naphthalene-1-carbonyl)-amino]-methyl}-benzyl)-carbamate O
H'k O
O N
Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 406 [M+H]+
(2) 6-amino-naphthalene-2-carboxylic acid-benzylamide O
N
H
H2N 5 Rf value: 0.83 (silica gel, ethyl acetate) (3) tert. Butyl {(3,5-dichloro-phenylsulphonyl))-[5-(pyrrolidine-1-carbonyl)-naphthalen-2-yl]-amino}-acetate O N'D
N
0=s=0 CI CI
io Mass spectrum (ESI+): m/z = 563, 565, 567 [M+H]+
(4) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-isopropylaminocarbonyl-naphthalen-2-yl)-amino]-acetate H
O N`11 N
0=s=0 CI CI
15 Mass spectrum (ESI+): m/z = 551, 553, 555 [M+H]+
(5) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-hydroxy-ethylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate H
O N~~OH
O fO
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 553, 555, 557 [M+H]+
Example IV
Methyl [[5-(4-aminomethyl-benzylaminocarbonyl)-naphthalen-2-yll-(3,5-dichloro-phenylsuIphonyl)-aminol-acetate H NHZ
O
I
O
N
O=s=0 CI I & CI
4 ml isopropanolic hydrochloric acid (5-6M) are added to 500 mg methyl [{5-io [4-(tert.-butoxycarbonylamino-methyl)-benzylaminocarbonyl]-naphthalen-2-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetate in 15 ml methylene chloride and the reaction mixture is stirred for 4 h at ambient temperature. For working up the reaction mixture is combined with some water and saturated sodium carbonate solution and extracted with methylene chloride. The combined extracts are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is stirred with tert.-butylmethyl ether, suction filtered, washed with tert.-butylmethylether and dried in the desiccator.
Yield: 375 mg (88 % of theory) Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
Example V
6-amino-naphthalene-1-carboxylic acid-methylamide H
5.40 ml diisopropylethylamine and 5.30 g O-(benzotriazol-1-yl)-1,1,3,3-tetram ethyluronium-tetrafluoroborate are added to 3.00 g 6-aminonaphthoic acid in 35 ml N,N-dimethylformamide. After ten minutes 12.02 ml methylamine solution (2M in tetrahydrofuran) are added and the reaction mixture is stirred overnight at ambient temperature. For working up the io reaction mixture is diluted with 150 ml of ethyl acetate and washed with water. The organic phase is extracted with 1 N hydrochloric acid. The combined aqueous extracts are made alkaline and extracted with ethyl acetate. The combined ethyl acetate-extracts are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is stirred with a little ethyl acetate, suction filtered, washed and dried.
Yield: 2.15 g (67 % of theory) Rf value: 0.40 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 201 [M+H]+
The following compounds are obtained analogously to Example V:
(1) tert. Butyl [[5-(cyclohexylmethyl-aminocarbonyl)-naphthaIen-2-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate O N
N
O=s=0 ciJ CI
(2) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylaminocarbonyl-naphthalen-2-yl)-amino]-acetate H
O N ,,O
N
O=s=0 CI CI
(3) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3,4-dihydro-1 H-isoquinoline-2-carbonyl)-naphthalen-2-yl]-amino}-acetate O O
N
O=s=0 CI CI
(4) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylethyl aminocarbonyl-io naphthalen-2-yl)-amino]-acetate H
O N
N
O=s=0 CI Cl (5) tert. Butyl [[5-(N-benzyl-N-methyl-aminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate I ~
O N
O O
N
O=s=O
ciJ CI
(6) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-(2-h yd roxy-eth yl)-a m id e O
N~iOH
HN I ~ / H
0=s=0 CI d CI
Rf value: 0.50 (silica gel, ethyl acetate) (7) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-phenylamide \
N
HN I / H
0=s=0 CI CI
(8) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-methylamide N
HN I ~ / H
O=s=O
CI d CI
Rf value: 0.71 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 409, 411, 413 [M+H]+
(9) 6-(3,5-dimethyl-phenylsulphonylamino)-naphthalene-2-carboxylic acid-5 benzylamide O
j(~e N~
HN I ~ ~ H
O=s=0 J: ~
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 445 [M+H]+
10 (10) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-benzylamide H
O N /
HN,S cl cl Rf value: 0.68 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 485, 487, 489 [M+H]+
(11) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-methylamide H
HN,S ci cl Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 409, 411, 413 [M+H]+
(12) 5-(3,5-dichloro-phenyllsulphonylamino)-naphthalene-1 -carboxylic acid-phenylamide H
O cC
HN,S cl cl Rf value: 0.81 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 471, 473, 475 [M+H]+
(13) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-phenylethylamide H
O ~7C
HN,S' cl O
cl Rf value: 0.27 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 499, 501, 503 [M+H]+
(14) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-2-methoxy-benzylamide H
O N
O~
HN,0 cl cl Rf value: 0.59 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 515, 517, 519 [M+H]+
(15) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-3-methoxy-benzylamide H
HN,S cl O
cl Rf value: 0.54 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 515, 517, 519 [M+H]+
(16) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-4-methoxy-benzylamide O~
H
O N
HN, 1, cl O
cl Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 515, 517, 519 [M+H]+
(17) 4-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-benzylamide O
H
O N
HN,O CI
O
CI
Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 483, 485, 487 [M-H]-(18) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-3-io aminocarbonyl-benzylamide O N O
NHZ
HN,S0 CI
O
CI
Rf value: 0.48 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 528, 530, 532 [M+H]+
(19) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-(pyridin-4-ylmethyl)-amide N
O N
HN
0=s=0 CI
CI
Mass spectrum (ESI+): m/z = 486, 488, 490 [M+H]+
(20) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-(pyridin-3-ylmethyl)-amide H
O N N
HN
0=s=0 Cl CI
Mass spectrum (ESI+): m/z = 486, 488, 490 [M+H]+
(21) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-io (morpholine-4-carbonyl)-benzylamide O
H I ~I
HN,0 ci CI
Rf value: 0.45 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 598, 600, 602 [M+H]+
(22) ethyl 4-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoate H
O N
HN, 1, cl O
cl Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(23) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-aminocarbonyl-benzylamide H NHZ
O N
HN, ,0 cl O
cl Rf value: 0.42 (silica gel, ethyl acetate) io Mass spectrum (ESI+): m/z = 528, 530, 532 [M+H]+
(24) tert.-butyl 4-[4-({[6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate O
N I ON H O
O
HN
o=s=o ciJ CI
Mass spectrum (ESI+): m/z = 697, 699, 701 [M+H]+
(25) ethyl 4-({[6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoate H IO
O
HN
o=s=o ciJ CI
Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(26) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-io (morpholine-4-carbonyl)-benzylamide O
N
H
O
O
HN
o=s=o Cl CI
Mass spectrum (ESI+): m/z = 598, 600, 602 [M+H]+
(27) tert.-butyl 4-[4-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate O ON
H O N 'f O-~
O
HN,S0 ci O
CI
Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 697, 699, 701 [M+H]+
(28) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-(morpholin-4-ylcarbonyl)-benzylamide /
O N I O
CN
O
HN,S0 CI
O
CI
Rf value: 0.46 (silica gel, ethyl acetate) io Mass spectrum (ESI+): m/z = 598, 600, 602 [M+H]+
(29) methyl 3-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoate /
O N I O
HN, 1, CI
O
CI
Rf value: 0.55 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(30) tert.-butyl 4-[3-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate CN~
N
HN, 1, O
CI
Rf value: 0.74 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 685, 697, 699 [M-H]-io (31) tert.-butyl 4-[2-({[6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate H
O N
O N
HN
O=s=0 0 CI
CI
Mass spectrum (ESI+): m/z = 697, 699, 701 [M+H]+
(32) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-2-(morpholin-4-ylcarbonyl)-benzylamide H
O N
O
HN,S CI
O
CI
Rf value: 0.18 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 598, 600, 602 [M+H]+
(33) tert.-butyl 4-[2-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate H
O N
O N
N'-( O
HN, " CI O
O
CI
Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 697, 699, 701 [M+H]+
(34) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-dimethylaminocarbonyl-benzylamide H
O N N~
HN, 1, CI
O
CI
Rf value: 0.45 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 556, 558, 560 [M+H]+
(35) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-dimethylaminocarbonyl-benzylamide N
O N
HN,0 ci CI
5 Rf value: 0.33 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 556, 558, 560 [M+H]+
KIN- ~~ YCI
O OS
CI
Rf value: 0.46 (silica gel, cyclohexane/ethyl acetate = 4:1) 5 (36) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate 00 I N 0~
N
O=s=0 CI I CI
Rf value: 0.80 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 606, 608, 610 [M+H]+
(37) tert. Butyl {[6-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino}-acetate Y O-N
N
O=s=0 CI I CI
Rf value: 0.86 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(38) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenyloxymethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate Y O-N~
OO N
O
N
O=s=0 CI I CI
Rf value: 0.82 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 640, 642, 644 [M+H]+
(39) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenylsulphonylmethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetate Y O-N
O DNS S.'O
N O
I /
o=s=o CI I / CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 688, 690, 692 [M+H]+
(40) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetate N-O
N
O
O ci OS
CI
(41) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-4-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetate N
H
O N
O~N. 'O cl ,S
O
:;f cl Rf value: 0.30 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(42) (66) tert. Butyl [[5-(cyclohexylmethyl-aminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate H
O N
O
O~N. 'O cl ,S
O
:;f cl Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate/acetic acid =
70:30:0.1) io Mass spectrum (ESI+): m/z = 605, 607, 609 [M+H]+
(43) tert. Butyl ((3,5-dichloro-phenylsuIphonyl)-{5-[(pyridin-2-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetate H
O N
n-N
O~N. 'O cl ,S
O
:;f cl Rf value: 0.52 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(44) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetate H
O N N
I
O
Oit",. 'O cl ,S
O :;f cl Rf value: 0.37 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(45) tert. Butyl [(3,5-dibromo-phenylsulphonyl)-(naphthalen-1-yl)-amino]-io acetate c O
O)_"' N Br OS / I
Br Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 571, 573, 575 [M+NH4]+
(46) tert. Butyl [(3-bromo-5-methyl-phenylsulphonyl)-(naphthalen-1 -yl)-amino]-acetate O
llu~N` , O O
OS -C;), Br Rf value: 0.68 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 507, 509 [M+NH4]+
(47) tert. Butyl [(3-bromo-5-chloro-phenylsulphonyl)-(naphthalen-1 -yl)-amino]-acetate CI
OS /
Br Rf value: 0.74 (silica gel, petroleum ether/ethyl acetate = 7:3) 5 Mass spectrum (ESI+): m/z = 527, 529, 531 [M+NH4]+
(48 tert. Butyl) [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N
H
O N
I
O
N` 1O CI
O OS / I
CI
1o Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(49) tert. Butyl [[5-(3-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate O N
N
O
O~N. '~ CI
S / I
CI
Rf value: 0.53 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(50) tert. Butyl [[5-(2-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate H
O N
N
Oit", N` 1O 0 CI
,S
O :;f CI
Rf value: 0.63 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 622, 624, 626 [M-H]-io (51) tert. Butyl [(2-cyano-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N N `gO 10 CYcl O
O O
CI
Rf value: 0.38 (silica gel, petroleum ether/ethyl acetate = 5:1) (52) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetate H
O~
I
Oit", N. 'O 0 CI
,S
O :;f CI
Rf value: 0.77 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(53) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetate /I
H N
O
O~N. 'O CI
,S /
O
CI
Rf value: 0.74 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
io (54) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetate O~
H
O N
II N \ 0 CI
s ' 1::
CI
Rf value: 0.68 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(55) tert. Butyl [[3-(phenylsulphonyl-methyl-amino)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate o=s=o N
YCI
o OS
CI
Mass spectrum (ESI+): m/z = 652, 654, 656 [M+NH4]+
(56) N-(4-amino-naphthalen-2-yl)-N-methyl-phenylsulphonamide o=s=o N
(57) tert. Butyl [(4-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate H
O N
O~N. '~ CI
S/ I
CI
io Mass spectrum (ESI+): m/z = 599, 601, 603 [M+H]+
(58) tert. Butyl [[5-(3-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate O N O
NHZ
O~N` '~ CI
S/
CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 642, 644, 646 [M+H]+
5 (59) tert. Butyl ((3,5-dichloro-phensulphonyl)-{5-[(pyridin-4-ylmethyl)-am inocarbonyl]-naphthalen-2-yl}-amino)-acetate "N
O N ~~
OO
N
o=s=o ciJ CI
Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
io (60) tert. Butyl ((3,5-dichloro-phensulphonyl)-{5-[(pyridin-3-ylmethyl)-am inocarbonyl]-naphthalen-2-yl}-amino)-acetate H
O N
OO
N
o=s=o ciJ Cl Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
15 (61) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[4-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetate N O
O
O~N` ~ CI
CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 712, 714, 716 [M+H]+
5 (62) tert. Butyl [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate H NHZ
O N
O
O~N` g ~ CI
O
CI
Rf value: 0.48 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 642, 644, 646 [M+H]+
(63) tert.-butyl 4-{4-[({6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate Fi 0 O
~N
0=s=0 ciJ CI
Mass spectrum (ESI+): m/z = 811, 813, 815 [M+H]+
(64) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[4-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-2-yl}-amino)-acetate O
N
H I
O
O
N
0=s=0 ciJ Cl Mass spectrum (ESI+): m/z = 712, 714, 716 [M+H]+
(65) tert.-butyl 4-{4-[({5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-io phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate O ON
H O N 'f 0-~
O
O
~ CI
CI
Rf value: 0.75 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 811, 813, 815 [M+H]+
(66) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[3-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetate O N O
1 CN) O
O~N` '~ CI S-q O
CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 729, 731, 733 [M+NH4]+
(67) tert.-butyl 4-{3-[({5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-1o phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate O N O
CN ~
N
O
, CI 0 0 /I\~ N` 1S'q O
CI
Rf value: 0.73 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 828, 830, 832 [M+NH4]+
(68) tert.-butyl 4-{2-[({6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate N /
O N
N O
N
O=s=0 0 ciJ CI
Mass spectrum (ESI+): m/z = 811, 813, 815 [M+H]+
(69) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{5-[2-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetate N
O N
O
O
O~N. '~ CI
S/
CI
Rf value: 0.32 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 712, 714, 716 [M+H]+
io (70) tert.-butyl 4-{2-[({5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carbonyl}-amino)-methyl]-benzoyl}-piperazine-1-carboxylate N
O N
O N
0 ~NUO\/
~N,~
OS
CI
Rf value: 0.56 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 811, 813, 815 [M+H]+
(71) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetate H
O N N
I
O~N. 'O CI
S
O
CI
Rf value: 0.42 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 670, 672, 674 [M+H]+
(72) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetate N
O N
O"U~ N CI
CI
Rf value: 0.58 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 670, 672, 674 [M+H]+
(73) tert. Butyl {[5-(2-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino}-acetate H
O N
O NHZ
O
ON. 0 CI
O
CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 642, 644, 646 [M+H]+
5 (74) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-methylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetate O"U~ N` cI1cI
CI
Rf value: 0.33 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(75) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-methylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetate H H
O N N
I
O~N. 'O 0 CI
O
CI
Rf value: 0.33 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(76) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate N
O N
O O
N
O=s=0 ciJ CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 687, 689, 691 [M+NH4]+
(77) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-dimethylaminocarbonyl-io benzylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate H
0 N ~ NII
N
O=s=0 CI
CI
Rf value: 0.45 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 687, 689, 691 [M+NH4]+
(78) tert. Butyl [[3-(N-benzyl-N-methyl-aminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate :N
NIs CI
O ,S
O
CI
Rf value: 0.48 (silica gel, cyclohexane/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+NH4]+
(79) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-[3-(N-methyl-N-phenyl-aminocarbonyl)-naphthalen-1-yl]-acetate N
/ CI
O OS
CI
Rf value: 0.67 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 616, 618, 620 [M+NH4]+
(80) benzyl 5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carboxylate o Oit", N. 'O 0 CI
,S
O :;f CI
Rf value: 0.95 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 617, 619, 621 [M+NH4]+
(81) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-trifluoromethanesulphonyloxy-naphthalen-1-yl)-amino]-acetate F
O -SF
O" F
O
~N 1O CI
yo OS /
CI
Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 631, 633, 635 [M+NH4]+
(82) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-quinolin-8-yl-amino]-acetate O n-NN
KI N` 10 , CI
S/
CI
Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate = 4:1) Mass spectrum (ESI+): m/z = 467, 469, 471 [M+H]+
(83) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-methoxy-quinolin-8-yl)-amino]-acetate I
O ccI
)1_1 N, CI
S/
CI
Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 497, 499, 501 [M+H]+
Example II
6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-cyano-benzylamide N
N
O
HN
O=s=0 CI I CI
2.21 g 3,5-dichlorophenylsulphonyl chloride are added to a solution of 2.50 g 6-amino-naphthalene-1-carboxylic acid-4-cyano-benzylamide dissolved in 40 ml of pyridine while cooling with an ice bath. After one hour the ice bath is removed and the reaction mixture is stirred for another two hours at ambient temperature. Then the pyridine is distilled off in vacuo, the flask residue is io taken up in methylene chloride, washed with 2N hydrochloric acid and water, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/ethyl acetate (9:1 to 8:2) as eluant.
Yield: 3.53 g (83 % of theory) Rf value: 0.31 (silica gel, methylene chloride/ethyl acetate = 9:1) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
The following compounds are obtained analogously to Example II:
(1) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-benzylamide O H
HN
O=s=0 CI I Cl Rf value: 0.53 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 485, 487, 489 [M+H]+
(2) tert. Butyl [4-({[6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-5 carbonyl]-amino}-methyl)-benzyl]-carbamate O
H~0 O N~
HN
O=s=0 CI I CI
Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 612, 614, 616 [M-H]-10 (3) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-methylamide H
O N~
HN
O=s=0 CI Cl Rf value: 0.65 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 407, 409, 411 [M-H]-(4) benzyl 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylate O O
HN
O=s=O
CI I d CI
Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate = 1:1) (5) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid icn-11 OH
HN
O=s=O
CI I CI
Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-(6) 3,5-dichloro-N-naphthalen-1-yl-phenylsulphonamide HN, 1, ci O /I
CI
Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESI-): m/z = 350, 352, 354 [M-H]-(7) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-benzylamide O
N
H
HN
O=s=0 CI I d CI
Rf value: 0.77 (silica gel, hexane/ethyl acetate = 1:2) (8) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid O OH
HN
O=s=0 CI CI
Rf value: 0.45 (silica gel, methylene chloride/methanol = 9:1) (9) 6-(3,5-dimethyl-phenylsulphonylamino)-naphthalene-1-carboxylic acid-benzylamide O N
HN
O=s=0 Rf value: 0.27 (silica gel, hexane/ethyl acetate = 1:1) (10) 6-(3,5-dimethyl-phenylsulphonylamino)-naphthalene-2-carboxylic acid-benzylamide Jcn--~ OH
HN
O=s=O
Jtl' Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 356 [M+H]+
(11) N-(7-amino-naphthalen-2-yl)-3,5-dichloro-phenylsulphonamide H N = NHZ
O=s=0 CI CI
Mass spectrum (ESI-): m/z = 365, 367, 369 [M-H]-(12) 3,5-dichloro-N-(6-hydroxy-naphthalen-2-yl)-phenylsulphonamide OH
HN
O=s=O
ciJ CI
Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 368, 370, 372 [M+H]+
(13) methyl 7-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylate HN-'~ O
O=s=O 0~
CI CI
Mass spectrum (ESI+): m/z = 410, 412, 414 [M+H]+
(14) 3,5-dichloro-N-(4-methoxy-naphthalen-2-yl)-phenylsulphonamide O' HN
O=s=O
CI I CI
Rf value: 0.80 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 382, 384, 386 [M+H]+
(15) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid O OH
I
HN,S ci CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-(16) N-(5-amino-naphthalen-1-yl)-3,5-dichloro-phenylsulphonamide NHZ
I
HN,S ci CI
Rf value: 0.34 (silica gel, petroleum ether/ethyl acetate = 2:1) (17) 3,5-dichloro-N-(6-pyrimidin-2-yl-naphthalen-2-yl)-phenylsulphonamide N
HN \ \ N
/ /
O=s=0 ciJ CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 430, 432, 434 [M+H]+
5 (18) 3,5-dichloro-N-(5-pyrimidin-2-yl-naphthalen-1-yl)-phenylsulphonamide n N XN
HN, 1, ci /I
CI
Rf value: 0.20 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 430, 432, 434 [M+H]+
io (17) (3,5-dichloro-N-(6-methoxy-naphthalen-1 -yl)-phenylsulphonamide HN,0 Cl CI
Rf value: 0.26 (silica gel, cyclohexane/ethyl acetate = 4:1) Mass spectrum (ESI+): m/z = 382, 384, 386 [M+H]+
15 (18) 3,5-dibromo-N-naphthalen-1-yl-phenylsulphonamide '0 HN, Br Br Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 3:2) Mass spectrum (ESI-): m/z = 438, 440, 442 [M-H]-(19) 3-bromo-5-methyl-N-naphthalen-1-yl-phenylsulphonamide HN11, /I
Br Rf value: 0.69 (silica gel, petroleum ether/ethyl acetate = 3:2) Mass spectrum (ESI-): m/z = 374, 376 [M-H]-io (19) 3-bromo-5-chloro-N-naphthalen-1 -yl-phenylsulphonamide HN, 1, CI
/I
O
Br Rf value: 0.76 (silica gel, petroleum ether/ethyl acetate = 3:2) Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-(29) 3,5-dichloro-N-(2-cyano-naphthalen-1-yl)-phenylsulphonamide HN`S1 ~ifcI
CI
(30) N-[3-(phenylsulphonyl-methyl-amino)-naphthalen-1-yl]-3,5-dichloro-phenylsulphonamide I~
O=s=O
N
HN,S,, cI
O
CI
Mass spectrum (ESI-): m/z = 519, 521, 523 [M-H]-(31) 4-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid O OH
I
HN,0 CI
O
CI
Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-(32) 4-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid OH
O
HN,9, cI
O
CI
Mass spectrum (ESI+): m/z = 413 [M+NH4]+
(33) 3,5-dichloro-N-(5-hydroxy-naphthalen-1-yl)-phenylsulphonamide OH
HN,0 CI
CI
Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI-): m/z = 366, 368, 370 [M-H]-(34) 3,5-dichloro-N-quinolin-8-yl-phenylsulphonamide O
CI \ S-NH
I / o CI
Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 353, 355, 357 [M+H]+
(35) [(3,5-dichloro-N-(6-methoxy-quinolin-8-yl)-phenylsulphonamide ccI
H
NCI
CI
Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 383, 385, 387 [M+H]+
Example III
6-amino-naphthalene-1-carboxylic acid-benzylamide H
N
1.49 g 1-hydroxybenzotriazole, 3.53 g O-(benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium-tetrafluoroborate, 6.93 ml triethylamine and 1.20 ml benzylamine are added under an argon atmosphere to 1.87 g 6-aminonaphthoic acid in a mixture of 20 ml of tetrahydrofuran and 20 ml N,N-dimethylformamide. The light brown solution is stirred for 3 h at ambient io temperature. Then the solvent is distilled off using the rotary evaporator, the flask residue is slowly combined with ice water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with 2N citric acid and saturated sodium chloride solution. A precipitate is formed which is suction filtered, washed with water and ethyl acetate and dried. The filtrate is combined with a little methanol, the organic phase is separated off, dried on magnesium sulphate and evaporated down. The flask residue is combined with the suction filtered precipitate, stirred with ethyl acetate, suction filtered, washed with some ethyl acetate and diethyl ether and dried in the desiccator.
Yield: 1.81 g (66 % of theory) Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 277 [M+H]+
The following compounds are obtained analogously to Example III:
(1) tert. Butyl (4-{[(6-amino-naphthalene-1-carbonyl)-amino]-methyl}-benzyl)-carbamate O
H'k O
O N
Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 406 [M+H]+
(2) 6-amino-naphthalene-2-carboxylic acid-benzylamide O
N
H
H2N 5 Rf value: 0.83 (silica gel, ethyl acetate) (3) tert. Butyl {(3,5-dichloro-phenylsulphonyl))-[5-(pyrrolidine-1-carbonyl)-naphthalen-2-yl]-amino}-acetate O N'D
N
0=s=0 CI CI
io Mass spectrum (ESI+): m/z = 563, 565, 567 [M+H]+
(4) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-isopropylaminocarbonyl-naphthalen-2-yl)-amino]-acetate H
O N`11 N
0=s=0 CI CI
15 Mass spectrum (ESI+): m/z = 551, 553, 555 [M+H]+
(5) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-hydroxy-ethylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate H
O N~~OH
O fO
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 553, 555, 557 [M+H]+
Example IV
Methyl [[5-(4-aminomethyl-benzylaminocarbonyl)-naphthalen-2-yll-(3,5-dichloro-phenylsuIphonyl)-aminol-acetate H NHZ
O
I
O
N
O=s=0 CI I & CI
4 ml isopropanolic hydrochloric acid (5-6M) are added to 500 mg methyl [{5-io [4-(tert.-butoxycarbonylamino-methyl)-benzylaminocarbonyl]-naphthalen-2-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetate in 15 ml methylene chloride and the reaction mixture is stirred for 4 h at ambient temperature. For working up the reaction mixture is combined with some water and saturated sodium carbonate solution and extracted with methylene chloride. The combined extracts are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is stirred with tert.-butylmethyl ether, suction filtered, washed with tert.-butylmethylether and dried in the desiccator.
Yield: 375 mg (88 % of theory) Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
Example V
6-amino-naphthalene-1-carboxylic acid-methylamide H
5.40 ml diisopropylethylamine and 5.30 g O-(benzotriazol-1-yl)-1,1,3,3-tetram ethyluronium-tetrafluoroborate are added to 3.00 g 6-aminonaphthoic acid in 35 ml N,N-dimethylformamide. After ten minutes 12.02 ml methylamine solution (2M in tetrahydrofuran) are added and the reaction mixture is stirred overnight at ambient temperature. For working up the io reaction mixture is diluted with 150 ml of ethyl acetate and washed with water. The organic phase is extracted with 1 N hydrochloric acid. The combined aqueous extracts are made alkaline and extracted with ethyl acetate. The combined ethyl acetate-extracts are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is stirred with a little ethyl acetate, suction filtered, washed and dried.
Yield: 2.15 g (67 % of theory) Rf value: 0.40 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 201 [M+H]+
The following compounds are obtained analogously to Example V:
(1) tert. Butyl [[5-(cyclohexylmethyl-aminocarbonyl)-naphthaIen-2-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate O N
N
O=s=0 ciJ CI
(2) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylaminocarbonyl-naphthalen-2-yl)-amino]-acetate H
O N ,,O
N
O=s=0 CI CI
(3) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3,4-dihydro-1 H-isoquinoline-2-carbonyl)-naphthalen-2-yl]-amino}-acetate O O
N
O=s=0 CI CI
(4) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylethyl aminocarbonyl-io naphthalen-2-yl)-amino]-acetate H
O N
N
O=s=0 CI Cl (5) tert. Butyl [[5-(N-benzyl-N-methyl-aminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate I ~
O N
O O
N
O=s=O
ciJ CI
(6) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-(2-h yd roxy-eth yl)-a m id e O
N~iOH
HN I ~ / H
0=s=0 CI d CI
Rf value: 0.50 (silica gel, ethyl acetate) (7) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-phenylamide \
N
HN I / H
0=s=0 CI CI
(8) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-methylamide N
HN I ~ / H
O=s=O
CI d CI
Rf value: 0.71 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 409, 411, 413 [M+H]+
(9) 6-(3,5-dimethyl-phenylsulphonylamino)-naphthalene-2-carboxylic acid-5 benzylamide O
j(~e N~
HN I ~ ~ H
O=s=0 J: ~
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 445 [M+H]+
10 (10) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-benzylamide H
O N /
HN,S cl cl Rf value: 0.68 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 485, 487, 489 [M+H]+
(11) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-methylamide H
HN,S ci cl Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 409, 411, 413 [M+H]+
(12) 5-(3,5-dichloro-phenyllsulphonylamino)-naphthalene-1 -carboxylic acid-phenylamide H
O cC
HN,S cl cl Rf value: 0.81 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 471, 473, 475 [M+H]+
(13) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-phenylethylamide H
O ~7C
HN,S' cl O
cl Rf value: 0.27 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 499, 501, 503 [M+H]+
(14) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-2-methoxy-benzylamide H
O N
O~
HN,0 cl cl Rf value: 0.59 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 515, 517, 519 [M+H]+
(15) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-3-methoxy-benzylamide H
HN,S cl O
cl Rf value: 0.54 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 515, 517, 519 [M+H]+
(16) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-4-methoxy-benzylamide O~
H
O N
HN, 1, cl O
cl Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 515, 517, 519 [M+H]+
(17) 4-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-benzylamide O
H
O N
HN,O CI
O
CI
Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 483, 485, 487 [M-H]-(18) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-3-io aminocarbonyl-benzylamide O N O
NHZ
HN,S0 CI
O
CI
Rf value: 0.48 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 528, 530, 532 [M+H]+
(19) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1 -carboxylic acid-(pyridin-4-ylmethyl)-amide N
O N
HN
0=s=0 CI
CI
Mass spectrum (ESI+): m/z = 486, 488, 490 [M+H]+
(20) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-(pyridin-3-ylmethyl)-amide H
O N N
HN
0=s=0 Cl CI
Mass spectrum (ESI+): m/z = 486, 488, 490 [M+H]+
(21) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-io (morpholine-4-carbonyl)-benzylamide O
H I ~I
HN,0 ci CI
Rf value: 0.45 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 598, 600, 602 [M+H]+
(22) ethyl 4-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoate H
O N
HN, 1, cl O
cl Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(23) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-aminocarbonyl-benzylamide H NHZ
O N
HN, ,0 cl O
cl Rf value: 0.42 (silica gel, ethyl acetate) io Mass spectrum (ESI+): m/z = 528, 530, 532 [M+H]+
(24) tert.-butyl 4-[4-({[6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate O
N I ON H O
O
HN
o=s=o ciJ CI
Mass spectrum (ESI+): m/z = 697, 699, 701 [M+H]+
(25) ethyl 4-({[6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoate H IO
O
HN
o=s=o ciJ CI
Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(26) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-io (morpholine-4-carbonyl)-benzylamide O
N
H
O
O
HN
o=s=o Cl CI
Mass spectrum (ESI+): m/z = 598, 600, 602 [M+H]+
(27) tert.-butyl 4-[4-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate O ON
H O N 'f O-~
O
HN,S0 ci O
CI
Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 697, 699, 701 [M+H]+
(28) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-(morpholin-4-ylcarbonyl)-benzylamide /
O N I O
CN
O
HN,S0 CI
O
CI
Rf value: 0.46 (silica gel, ethyl acetate) io Mass spectrum (ESI+): m/z = 598, 600, 602 [M+H]+
(29) methyl 3-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoate /
O N I O
HN, 1, CI
O
CI
Rf value: 0.55 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(30) tert.-butyl 4-[3-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate CN~
N
HN, 1, O
CI
Rf value: 0.74 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 685, 697, 699 [M-H]-io (31) tert.-butyl 4-[2-({[6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate H
O N
O N
HN
O=s=0 0 CI
CI
Mass spectrum (ESI+): m/z = 697, 699, 701 [M+H]+
(32) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-2-(morpholin-4-ylcarbonyl)-benzylamide H
O N
O
HN,S CI
O
CI
Rf value: 0.18 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 598, 600, 602 [M+H]+
(33) tert.-butyl 4-[2-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoyl]-piperazine-1-carboxylate H
O N
O N
N'-( O
HN, " CI O
O
CI
Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 697, 699, 701 [M+H]+
(34) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-dimethylaminocarbonyl-benzylamide H
O N N~
HN, 1, CI
O
CI
Rf value: 0.45 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 556, 558, 560 [M+H]+
(35) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-dimethylaminocarbonyl-benzylamide N
O N
HN,0 ci CI
5 Rf value: 0.33 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 556, 558, 560 [M+H]+
(36) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-2-aminocarbonyl-benzylamide H
HNI " CI
O
Rf value: 0.63 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 528, 530, 532 [M+H]+
HNI " CI
O
Rf value: 0.63 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 528, 530, 532 [M+H]+
(37) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-15 methylaminocarbonyl-benzylamide HN,0 ci CI
Rf value: 0.46 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 542, 544, 546 [M+H]+
Rf value: 0.46 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 542, 544, 546 [M+H]+
(38) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-methylam inocarbonyl-benzylamide H H
O N N
HN, 1, CI
O
CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 542, 544, 546 [M+H]+
O N N
HN, 1, CI
O
CI
Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 542, 544, 546 [M+H]+
(39) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-dimethylaminocarbonyl-benzylamide O N N
HN
0=s=0 CI
CI
Rf value: 0.25 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 556, 558, 560 [M+H]+
HN
0=s=0 CI
CI
Rf value: 0.25 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 556, 558, 560 [M+H]+
(40) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-dimethylaminocarbonyl-benzylamide H
O N N
HN
O=s=0 ciJ CI
Rf value: 0.30 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 556, 558, 560 [M+H]+
O N N
HN
O=s=0 ciJ CI
Rf value: 0.30 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 556, 558, 560 [M+H]+
(41) 4-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-io benzyl-methyl-amide OiX~i HN,S, CI
O :;:, CI
Rf value: 0.55 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 516, 518, 520 [M+NH4]+
O :;:, CI
Rf value: 0.55 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 516, 518, 520 [M+NH4]+
(42) 4-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid-methyl-phenyl-amide aN
HN,9, cI
O
CI
Rf value: 0.23 (silica gel, cyclohexane/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 485, 487, 489 [M+H]+
HN,9, cI
O
CI
Rf value: 0.23 (silica gel, cyclohexane/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 485, 487, 489 [M+H]+
(43) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-{[6-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl]-aminocarbonyl}-naphthalen-1-yl)-amino]-acetate H
/ N
I
O H
N
O
N, 1O cl s O
O
cl Rf value: 0.22 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) 1o Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
/ N
I
O H
N
O
N, 1O cl s O
O
cl Rf value: 0.22 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) 1o Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
(44) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-aminocarbonyl}-naphthalen-1-yl)-amino]-acetate N
H I
O N NH
O
O~N. 'O cl ,S /
O
cl Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
H I
O N NH
O
O~N. 'O cl ,S /
O
cl Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
(45) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetate H
O\ N I Ni O
O~N. 'O CI
,S /
O
CI
Rf value: 0.25 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 700, 702, 704 [M+H]+
O\ N I Ni O
O~N. 'O CI
,S /
O
CI
Rf value: 0.25 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 700, 702, 704 [M+H]+
(46) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-({6-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-3-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetate / N
I
O H
N
O
O~N` 1~ CI
4 s O
CI
Rf value: 0.30 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 700, 702, 704 [M+H]+
I
O H
N
O
O~N` 1~ CI
4 s O
CI
Rf value: 0.30 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 700, 702, 704 [M+H]+
(47) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-{[6-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl]-aminocarbonyl}-naphthalen-2-yl)-amino]-acetate H
/I NNi O N N
O O
N
O=s=0 ciJ CI
Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
/I NNi O N N
O O
N
O=s=0 ciJ CI
Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
(48) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-aminocarbonyl)-naphthalen-2-yl]-amino}-acetate / N
H I
y O N NN
N
O=s=0 CI
Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 700, 702, 704 [M+H]+
15 (49) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-({6-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-3-ylmethyl}-aminocarbonyl)-naphthalen-2-yl]-amino}-acetate / N
y O N N
O O
N
O=s=0 ciJ CI
Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 700, 702, 704 [M+H]+
(50) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-carbamoyl}-naphthaIen-2-yl)-amino]-acetate / N I
H
O N NN
/XI O~O H
N
O=s=0 Cl CI
Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. Aqueous io ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
Example VI
6-ftert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-aminol-naphthalene-1-carboxylic acid Y O OH
O ~O
N
O=s=0 CI CI
350 mg benzyl 6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carboxylate are hydrogenated in 25 ml of tetrahydrofuran in the presence of 40 mg palladium on activated charcoal (10 %) at ambient temperature and at a partial hydrogen pressure of 0.38 bar for 4.5 h. Then the catalyst is filtered off and the filtrate is evaporated down.
The flask residue is dissolved slightly with a little tert-butylmethyl ether, diluted with petroleum ether, stirred, suction filtered, washed with petroleum ether and dried.
Yield: 291 mg (96 % of theory) io Rf value: 0.30 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 527, 529, 531 [M+NH4]+
The following compounds are obtained analogously to Example VI:
(1) 5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsuIphonyl)-amino]-naphthalene-1-carboxylic acid O OH
I
KIN-9, CI
OS
CI
Rf value: 0.25 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 527, 529, 531 [M+NH4]+
Example VII
Benzyl 6-amino-naphthalene-1-carboxylate O O I
1.00 g 6-aminonaphthoic acid is suspended in benzylalcohol, combined with 920 mg anhydrous p-toluenesulphonic acid and stirred for a few minutes in the oil bath at 80 C. Then 1.23 g p-toluenesulphonic acid chloride are added and the reaction mixture is stirred for 4 h at 80 C.
A further 600 mg p-toluenesulphonic acid chloride are added and the reaction mixture is stirred for a further 5 h at 80 -90 C. After cooling to ambient temperature the reaction mixture is diluted with 90 ml tert.-butyl methyl ether, the precipitate formed is suction filtered and washed with a little tert.-butylmethylether. The filter cake is taken up in tert.-butyl methyl ether and washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down.
io Yield: 242 mg (16 % of theory) Rf value: 0.85 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 278 [M+H]+
Example VIII
6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid amide HN
O=s=0 CI I d CI
A mixture of 10.00 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid, 24.30 g ammonium carbonate, 8.10 g O-(benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium-tetrafluoroborate and 3.52 ml triethylamine in 120 ml of tetrahydrofuran is stirred overnight at ambient temperature. For working up the reaction mixture is diluted with 150 ml of ethyl acetate and washed with 10 % citric acid solution, 1 N sodium hydroxide solution and saturated sodium chloride solution. The organic phase is dried on magnesium sulphate and evaporated down. The flask residue is stirred with diisopropylether, suction filtered and dried at 40 C in the circulating air dryer.
The sodium hydroxide solution phase is extracted with methylene chloride, during which time a precipitate is formed which is suction filtered and also dried in the circulating air dryer.
Yield: 7.13 g (72 % of theory) Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 393, 395, 397 [M-H]-The following compounds are obtained analogously to Example VIII:
(1) tert. Butyl [(5-aminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate O O
N
O=s=0 CI CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) (2) 7-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid amide HN-'~ O
O=S=O NH2 CI CI
Mass spectrum (ESI+): m/z = 395, 397, 399 [M+H]+
Example IX
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,41oxadiazol-3-yl)-naphthalen-2-yll-amino}-acetate X N-O
O I '-N
O=s=0 CI I Cl A mixture of 400 mg tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(N-hydroxy-carbamimidoyl)-naphthalen-2-yl]-amino}-acetate and 0.16 ml acetic anhydride in 5 ml acetonitrile is heated for five minutes in the microwave at 180 C. The reaction mixture is evaporated down, and the crude product is purified by chromatography through a silica gel column with cyclohexane/ethyl acetate (75:25 to 50:50) as eluant.
Yield: 250 mg (60 % of theory) Rf value: 0.90 (silica gel, cyclohexane/ethyl acetate = 1:1) The following compounds are obtained analogously to Example IX:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[7-(5-methyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate O
N I/ O~N.
O
0=s=0 Nom( ciJ CI
Mass spectrum (ESI+): m/z = 565, 567, 569 [M+NH4]+
(2) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-methyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate 0-~
NN N
O=s=0 CI CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 565, 567, 569 [M+NH4]+
(3) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-phenyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate OP
NN N
O O
O=s=0 ciJ CI
(reaction carried out with benzoyl chloride in 2,4,6-trimethylpyridine) Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 610, 612, 614 [M+H]+
(4) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-benzyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate O \ /
NN N
O O
O=s=0 CI I Cl io (reaction carried out with phenylacetyl chloride in 2,4,6-trimethylpyridine) Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(5) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate o~
NN N
N
O=s=0 CI CI
(reaction carried out with isobutyric acid chloride in 2,4,6-trimethylpyridine) Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 576, 578, 580 [M+H]+
(6) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-phenyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate Y N-O
N
0=s=0 (reaction carried out with benzoyl chloride in 2,4,6-trimethylpyridine and io methylene chloride) Rf value: 0.76 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 610, 612, 614 [M+H]+
(7) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-phenyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate Y N,0 N
O=s=0 Cl CI
(reaction carried out with phenylacetyl chloride in 2,4,6-trimethylpyridine and methylene chloride) Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(8) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate N-O
Y I
O 0 ~
N
CIC
N
O=s=0 CI J CI
(reaction carried out with isobutyric acid chloride in 2,4,6-trimethylpyridine and methylene chloride) 1o Rf value: 0.71 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 576, 578, 580 [M+H]+
(9) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-hydroxy-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate OH
0-~
NN N
N
O=s=O
CI CI
(formed as a by-product of the reaction with trichloroacetic acid chloride in 2,4,6-trimethylpyridine) Rf value: 0.30 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESI-): m/z = 548, 550, 552 [M-H]-(10) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate cI
cI
O i cI
N~ N
O O ~ --.:
N I / /
O=s=0 CI I / CI
(reaction carried out with trichloroacetic acid chloride in 2,4,6-tri methyl pyridine) Rf value: 0.70 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 667, 669, 671, 673 [M+NH4]+
(11) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetate o-/
N N
c O Os / q CI
1o Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 565, 567, 569 [M+NH4]+
(12) tert. Butyl [[5-(5-chloromethyl -[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate O-ccI
N N
O O
N \ \
O=s=0 CI
CI
(reaction carried out with chloroacetyl chloride in 2,4,6-trimethylpyridine and methylene chloride) Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 3:1) (13) 3-(5-bromo-naphthalen-2-yl)-5-methyl-[1,2,4]oxadiazole N-O
C;)O Al N i>-Br Rf value: 0.74 (silica gel, cyclohexane/ethyl acetate = 1:1) (14) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetate N
I
O
0-N (N`g' CI
O
CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 548, 550, 52 [M+H]+
Example X
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(N-hydroxycarbamimidoyl)-naphthalen-2-yll-amino}-acetate N.OH
NHZ
O O J:/ OI
N
O=s=0 CI CI
A mixture of 2.46 g tert. butyl [(6-cyano-naphthalen-2-yl)-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate, 750 mg hydroxylamine-hydrochloride and 1.58 ml triethylamine in 25 ml absolute ethanol is refluxed for 3 h. The precipitate formed is suction filtered, washed with diethyl ether and dried at 50 C in the circulating air dryer.
Yield: 1.57 g (60 % of theory) Rf value: 0.10 (silica gel, cyclohexane/ethyl acetate = 3:1) The following compounds are obtained analogously to Example X:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[7-(N-hydroxycarbamimidoyl)-naaphhthalen-2-yl]-amino}-acetate O
N N.OH
O=S=O NHZ
CI I CI
(2) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(N-hydroxycarbamimidoyl)-naphthalen-2-yl]-amino}-acetate OH
~ N NHZ
/O O
N
O=s=0 ciJ CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 524, 526, 528 [M+H]+
(3) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(N-hydroxycarbamimidoyl)-naphthalen-1-yl]-amino}-acetate OH
O~` ~ YCI
CI
Rf value: 0.38 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 524, 526, 528 [M+H]+
(4) [(5-aminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid CI
Rf value: 0.25 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 509, 511, 513 [M+H]+
(5) 5-bromo-N-hydroxy-naphthalene-2-carboxamidine N
I
PCYII~ NH2 Br Rf value: 0.54 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 265, 267 [M+H]+
(6) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[2-(N-hydroxycarbamimidoyl)-naphthalen-1-yl]-amino}-acetate I O
HO_N (N ;S' CI
O
CI
Rf value: 0.42 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 524, 526, 528 [M+H]+
Example XI
3,5-dichloro-N-(6-cyano-naphthalen-2-yl)-phenylsulphonamide N
H N I D
O=S=0 CI CI
1.48 ml trifluoroacetic anhydride are added dropwise to 3.43 g 6-(3,5-io dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid amide and 3.64 ml triethylamine in 130 ml methylene chloride while cooling with an ice bath. The reaction mixture is stirred for 3 h at ambient temperature, then another 1.48 ml trifluoroacetic anhydride are added dropwise while cooling with an ice bath. After another two hours at ambient temperature a further 1.48 ml trifluoroacetic anhydride are added and the reaction mixture is stirred overnight at ambient temperature. For working up the reaction mixture is combined with 70 ml of water. The organic phase is separated off, washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (75:25 to 50:50) as eluant.
Yield: 2.29 g (70 % of theory) Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESI-): m/z = 375, 377, 379 [M-H]-The following compounds are obtained analogously to Example XI:
(1) 3,5-dichloro-N-(7-cyano-naphthalen-2-yl)-phenylsulphonamide H N J
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 394, 396, 398 [M+NH4]+
(2) 3,5-dichloro-N-(5-cyano-naphthalen-2-yl)-phenylsulphonamide N
II
HN / /
O=s=0 CI I / CI
Rf value: 0.68 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 375, 377, 379 [M-H]-(3) 3,5-dichloro-N-(5-cyano-naphthalen-1-yl)-phenylsulphonamide N
II
HN.. " Cl /I
CI
Rf value: 0.86 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 375, 377, 379 [M-H]-Example XII
tert. Butyl [(3,5-dichloro-phenvlsulphonvl)-(6-oxazol-2-yl-naphthalen-2-yl)-aminol-acetate N
O
O=s=0 ciJ CI
A mixture of 1.43 g tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(2-oxo-ethyl-aminocarbonyl)-naphthalen-2-yl]-amino}-acetate and 620 mg Burgess reagent in 10 ml of tetrahydrofuran is heated to 170 C in the microwave for 5 min. The reaction mixture is evaporated down and chromatographed through io a silica gel column with cyclohexane/ethyl acetate (80:20 to 66:34) as eluant.
Yield: 179 mg (13 % of theory) Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 3:1) Example XIII
tert. Butyl {(3,5-dichloro-phenvlsulphonvl)-[6-(2-oxo-ethylaminocarbonyl)-naphthalen-2-yll-amino}-acetate N I / / H
O=s=0 CI CI
Prepared by oxidation of tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(2-2o hydroxy-ethylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate with Dess-Martin reagent in methylene chloride at ambient temperature.
Rf value: 0.70 (silica gel, ethyl acetate) Example XIV
6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsuIphonyl)-aminol-naphthalene-1-carboxylic acid X O OH
O fO
N
O=s=0 CI CI
0.64 ml trimethylsilyl chloride are added to 1.00 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid and 0.86 ml diisopropylethylamine in 10 ml of tetrahydrofuran while cooling with an ice bath. After ten minutes 2.10 g potassium-bis(trimethylsilyl)-amide are added io batchwise, and the reaction mixture is heated to ambient temperature. After 6 h at this temperature the reaction mixture is combined with 0.20 ml tert.
Butyl bromoacetate and stirred for a further 2 h at ambient temperature. For working up the reaction mixture is combined with 0.44 ml piperazine and 2 ml of methanol. After ten minutes 100 ml 1 N hydrochloric acid are added and the mixture is extracted with ethyl acetate. The organic phase is separated off, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/methanol (20:1 to 10:1) as eluant.
Yield: 730 mg (57 % of theory) Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1) Example XV
N-[7-(3,5-dichloro-phenylsulphonylamino)-naphthalen-2-yll-benzamide HN / / N H
CI CI
104 pl benzoyl chloride are added to 300 mg N-(7-amino-naphthalen-2-yl)-3,5-dichloro-phenylsulphonamide and 0.17 ml triethylamine in 5 ml methylene chloride while cooling with an ice bath. After heating to ambient temperature the reaction mixture is stirred for another 3 h. Then it is combined with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with dilute hydrochloric acid and saturated sodium hydrogen carbonate solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column.
Yield: 310 mg (81 % of theory) io Mass spectrum (ESI-): m/z = 469, 471, 473 [M-H]-The following compounds are obtained analogously to Example XV:
(1) tert. Butyl [{7-[(4-chloro-pyridine-2-carbonyl)-amino]-naphthalen-2-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N CI
N H
0=s=0 N
(2) tert. Butyl [(5-benzoylamino-naphthalen-1 -yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate HN
O
Rf value: 0.54 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI-): m/z = 583, 585, 587 [M-H]-(3) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylacetylamino-naphthalen-1-yl)-amino]-acetate /
HN
O
AO CI
CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI-): m/z = 597, 599, 601 [M-H]-(4) tert. Butyl {(3,5-dichloro-phenylsuIphonyl)-[5-(3-phenyl-prop ionylamino)-naphthalen-1-yl]-amino}-acetate O
HN
AO
~N` O CI
O
O s / I
CI
Rf value: 0.34 (silica gel, petroleum ether/ethyl acetate = 2:1) io Mass spectrum (ESI-): m/z = 611, 613, 615 [M-H]-(5) tert. Butyl [{5-[(4-chloro-pyridin-2-yl-carbonyl)-amino]-naphthalen-1-yl}-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate N
HN
CI
O
CI
Rf value: 0.64 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 620, 622, 624 [M+H]+
Example XVI
tert. Butyl [[7-(3-benzyl-ureido)-naphthalen-2-yll-(3,5-dichloro-phenylsulphonyl)-aminol-acetate NJ= N
0=s=0 H H
CI J CI
2 mg 4-dimethylaminopyridine and 18.5 pl benzylisocyanate are added to 60 mg tert. Butyl [(7-amino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate in 4 ml methylene chloride. The reaction mixture is stirred overnight at ambient temperature and then evaporated down in vacuo. The 1o crude product is purified by chromatography through a silica gel column.
Yield: 74 mg (97 % of theory) Mass spectrum (ESI-): m/z = 658, 660, 662 [M+HCOO]-The following compounds are obtained analogously to Example XVI:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-ureido)-naphthalen-1-yl]-amino}-acetate HN N
H
O
CI
Rf value: 0.78 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(2) tert. Butyl [[5-(3-benzyl-ureido)-naphthalen-1 -yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate O
HN N
A
I~ \
H
~N` O ci O S /
O
CI
Rf value: 0.65 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
Example XVII
tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-3-yl-naphthalen-2-vl)-aminol-acetate N
N
O=s=0 A mixture of 200 mg tert. butyl [(3,5-dichlorophenylsulphonyl)-(6-trifluoromethanesuIphonyloxy-naphthalen-2-yl)-amino]-acetate, 56 mg 3-pyridylboric acid and 69 mg sodium carbonate in 7 ml of toluene is combined with 0.80 ml of ethanol and 0.80 ml of water. The resulting solution is briefly evacuated twice and ventilated with argon. Then 56 mg of tetrakis-(triphenylphosphine)-palladium are added and the mixture is again evacuated and ventilated with argon. The reaction mixture is stirred for 7 h at 83 C and then slowly cooled overnight to ambient temperature. For working up the reaction mixture is mixed with water and extracted with ethyl acetate.
The organic phase is washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with petroleum ether/ethyl acetate (8:2 to 7:3).
Yield: 97 mg (55 % of theory) Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
The following compounds are obtained analogously to Example XVII:
(1) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-4-yl-naphthalen-2-yl)-amino]-acetate N
I
O O
O=s=0 (The reaction is carried out with pinacolyl 4-pyridinylborate.) 1o Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(2) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-furan-3-yl-naphthalen-2-yl)-amino]-acetate O o o N
O=s=0 ciJ CI
Rf value: 0.65 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESI+): m/z = 549, 551, 553 [M+NH4]+
(3) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3,5-dimethyl-isoxazol-4-yl)-2o naphthalen-2-yl]-amino}-acetate ,N
O
O=s=0 CI CI
Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESI+): m/z = 578, 580, 582 [M+NH4]+
(4) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-furan-2-yl-naphthalen-2-yl)-amino]-acetate N
O=s=0 ciJ CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESI+): m/z = 549, 551, 553 [M+NH4]+
(5) tert. Butyl (6-pyrimidin-2-yl-naphthalen-2-yl)-carbamate N
II O N
O I N
H
(The reaction takes place between 4-bromopyridine and 6-tert.-butoxycarbonyl amino-naphthalen-2-yl-boric acid in a mixture of 1,4-dioxane and methanol.) Rf value: 0.63 (silica gel, petroleum ether/ethyl acetate = 1:1) (6) tert. Butyl (5-pyrimidin-2-yl-naphthalen-1-yl)-carbamate N ~N
\\/ONH
TI O
(The reaction takes place between 4-bromopyridine and 5-tert.-butoxycarbonylamino-naphthalen-1-yl-boric acid in a mixture of 1,4-dioxane and methanol.) Rf value: 0.38 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 322 [M+H]+
(7) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-2-yl-naphthalen-2-yl)-amino]-acetate X /
O O
N
N
O=s=0 CI I / CI
(The reaction takes place with diisopropyl 2-pyridinylborate.) Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(8) tert.-butyl 4-(2-{6-[tert.-butoxycarbonylmethyl -(3,5-dichloro-phenylsulphonyl)-amino]-naphthalen-2-yl}-pyrimidin-4-yl)-piperazine-1-carboxylate N
N 3yO
O=s=0 0 ciJ CI
(The reaction takes place between tert.-butyl 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylate and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 728, 730, 732 [M+H]+
(9) tert.-butyl 4-(2-{5-[tert-butoxycarbonylm ethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalen-1-yl}-pyrimidin-4-yl)-piperazine-1-carboxylate rN~O
NJ
N ~N
N` O CI
O OS
CI
(The reaction takes place between tert.-butyl 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylate and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate.) Rf value: 0.65 (silica gel, tert.-butylmethylether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 728, 730, 732 [M+H]+
(10) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(2-morpholin-4-yl-pyrimidin-4-yl)-naphthalen-2-yl]-amino}-acetate O 0 icr(1c N
O=s=0 CI I CI
(The reaction takes place between 4-(4-chloro-pyrimidin-2-yl)-morpholine and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.65 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(11) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-{4-[N-(2-dimethylamino-ethyl)-N-methyl-amino]-pyrimidin-2-yl}-naphthalen-2-yl)-amino]-acetate N
Y
N \
O=s=0 N
ciJ CI
(The reaction takes place between N-(2-chloro-pyrimidin-4-yl)-N,N',N'-io trimethyl -ethane-1,2-diamine and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborol an-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.35 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 95:5:0.1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(12) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-1-yl]-amino}-acetate ~o NJ
N ~N
O
~N, 1O CI
O OS / I
CI
(The reaction takes place between 4-(2-chloro-pyrimidin-4-yl)-morpholine and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate.) Rf value: 0.22 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(13) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{6-[4-(2-dimethylamino-ethyl amino)-pyrimidin-2-yl]-naphtha len-2-yl}-amino)-acetate Y N
OTO ~N NH
N
O=s=0 N
ciJ CI
(The reaction takes place between N'-(2-chloro-pyrimidin-4-yl)-N,N-dimethyl-ethane-1,2-diamine and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-io (4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.28 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) (14) tert. Butyl [[5-(2-chloro-pyrimidin-4-yl)-naphthalen-1 -yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N I CI
SIN
O
O N, 1~ CI
S/
CI
(The reaction takes place between 2,4-dichloropyrimidine and tert. Butyl {(3,5-d ich loro-ph enylsu l phonyl)-[5-(4,4,5,5-tetramethyl-[1 ,3,2]d ioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate.) Rf value: 0.13 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 578, 580, 582 [M+H]+
(15) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(6-morpholin-4-yl-pyridazin-3-yl)-naphthalen-2-yl]-amino}-acetate rO
N NI-) OO
N
O=s=0 ciJ CI
(The reaction takes place between 4-(6-iodo-pyridazin-3-yl)-morpholine and 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-2-boric acid.) Rf value: 0.63 (silica gel, methylene chloride/methanol = 95:5) (16) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-io 5-yl)-naphthalen-1-yl]-amino}-acetate cI
N" N
I , P'O O ~ . 'CI
S
CI
Mass spectrum (ESI+): m/z = 578, 580, 582 [M+H]+
(The reaction takes place between 5-bromo-2-chloro-pyrimidine and tert.
Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate.) (17) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{6-[5-(2-dimethylamino-ethylamino)-pyrazin-2-yl]-naphtha len-2-yl}-amino)-acetate H
NYN
Y I
O N
O=s=0 ciJ CI
(The reaction takes place between N'-(5-bromo-pyrazin-2-yl)-N,N-dimethyl-ethane-1,2-diamine and 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-2-boric acid.) Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
io (18) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{6-[6-(2-dimethylamino-ethylamino)-pyridazin-3-yl]-naphtha len-2-yl}-amino)-acetate H
N N N
OO
N
O=s=0 ciJ Cl (The reaction takes place between N'-(6-bromo-pyridazin-3-yl)-N,N-dimethyl-ethane-1,2-diamine and 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenyl-sulphonyl)-amino]-naphthalene-2-boric acid.) Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) (19) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetate N
00 ~N
N \ \
O=s=0 ciJ CI
(The reaction takes place between 4-(2-chloro-4-pyrimidinyl)-morpholine and tert. butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(20) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-morpholin-4-yl-pyrazin-yl)-naphthalen-2-yl]-amino}-acetate ro /N
N I
N \ \
O=s=0 ciJ CI
(The reaction takes place between 4-(5-bromo-pyrazin-2-yl)-morpholine and 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-2-boric acid.) Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
Example XVIII
3,5-dichloro-N-(6-trifluoromethanesulphonyloxy-naphthalen-2-yl)-phenylsulphonamide HN / / O F F
O=s=0 CI I / CI
A solution of 0.36 ml trifluoromethanesulphonic acid anhydride in 5 ml methylene chloride is added dropwise to 760 mg of 3,5-dichloro-N-(6-hydroxy-naphthalen-2-yl)-phenylsulphonamide and 0.48 ml of pyridine in 25 ml methylene chloride while cooling with an ice bath, and the reaction mixture is slowly heated to ambient temperature. Then a further 0.20 ml of pyridine io and 0.10 ml trifluoromethanesulphonic acid anhydride are added while cooling with an ice bath. For working up the reaction mixture is diluted with methylene chloride, washed with dilute sodium carbonate solution, dilute hydrochloric acid and water, dried on magnesium sulphate and evaporated down. The flask residue is stirred with petroleum ether, the precipitate formed is suction filtered and dried.
Yield: 808 mg (78 % of theory) Rf value: 0.85 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 498, 500, 502 [M-H]-The following compounds are obtained analogously to Example XVIII:
(1) 3,5-dichloro-N-(5-trifluoromethanesulphonyloxy-naphthalen-1-yl)-phenylsulphonamide F
O F
0-S,. F
HN, 1, ci /I
CI
Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 517, 519, 521 [M+NH4]+
Example XIX
7-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid HN-'~ O
O=s=0 OH
CI CI
A mixture of 300 mg methyl 7-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylate, 10 ml of 2N sodium hydroxide solution and 10 io ml of methanol is stirred for 6 h at ambient temperature, then the solvent is distilled off in vacuo. The flask residue is acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are dried on magnesium sulphate and evaporated down. The crude product is extracted with diisopropylether, suction filtered and dried.
Yield: 277 mg (96% of theory) Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-The following compounds are obtained analogously to Example XIX:
(1) 4-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoic acid H / I OH
O N
I
HN, 1, CI
O
CI
Rf value: 0.56 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(2) 4-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carbonyl]-amino}-methyl)-benzoic acid H / I OH
O N
HN
O=s=O
ciJ CI
Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(3) 3-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoic acid /
OH
HN,S~ CI
O
CI
io Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
Example XX
6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid amide O NHZ
HN
O=s=0 CI I CI
2.90 g carbonyldiimidazole are added to 7.20 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid in 70 ml N,N-dimethylformamide and the reaction mixture is heated in a water bath. After cooling to ambient temperature the reaction mixture is stirred for another 5 h, combined with 20 ml concentrated ammonia and stirred overnight. Then the mixture is diluted with ethyl acetate, the organic phase is separated off and the aqueous phase is acidified with concentrated hydrochloric acid. A
precipitate settles out, which is suction filtered and dried.
Yield: 4.50 g (63 % of theory) io Mass spectrum (ESI+): m/z = 395, 397, 399 [M+H]+
The following compounds are obtained analogously to Example XX:
(1) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid amide HN, 1 , cl S-q cl Rf value: 0.20 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 395, 397, 399 [M+H]+
(2) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-(pyridin-4-ylmethyl)-amide N
O N
HN,0 cl cl (The reaction takes place with 4-picolylamine in tetrahydrofuran.) Rf value: 0.25 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 484, 486, 488 [M-H]-(3) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-cyclohexylmethyl-amide H
O N
HN,0 cl cl (The reaction takes place with aminomethylcyclohexane in tetrahydrofuran.) Rf value: 0.80 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 489, 491, 493 [M-H]-(4) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-(pyridin-2-ylmethyl)-amide H
O N
n-N
HN,0 cl cl (The reaction takes place with 2-picolylamine in tetrahydrofuran.) Rf value: 0.52 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 486, 488, 490 [M+H]+
(5) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-(pyridin-3-ylmethyl)-amide H
O N N
~
HN CI
CI
(The reaction takes place with 3-picolylamine in tetrahydrofuran.) Rf value: 0.30 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 484, 486, 488 [M-H]-(6) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-cyano-benzylamide N
H
O N
- I
HN, 1, CI
O
CI
(The reaction takes place with 4-cyanobenzylamine in tetrahydrofuran.) 1o Rf value: 0.90 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
(7) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-cyano-benzylamide O N
N
HN, 1, CI
O
CI
(The reaction takes place with 3-cyanobenzylamine in tetrahydrofuran.) Rf value: 0.90 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
(8) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-cyano-benzylamide H
O
i i NI
HN,0 CI
CI
(The reaction takes place with 2-cyanobenzylamine in tetrahydrofuran.) Rf value: 0.37 (silica gel, cyclohexane/ethyl acetate = 1:1) Example XXI
(3,5-dichloro-N-[5-(3-methyl-[1,2,41oxadiazol-5-yl)-naphthalen-2-yll-phenylsulphonamide N
O ,N
HN
O=s=0 CI I CI
185 mg N-hydroxy-acetamidine are added to 1.00 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl chloride in 2 ml 2,4,6-trimethylpyridine. The reaction mixture is heated to 110 C and stirred for 6 h at this temperature. After cooling to ambient temperature the mixture is combined with ethyl acetate and water. The organic phase is separated off and washed with 1 N hydrochloric acid, water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue stirred is with methylene chloride, suction filtered and dried.
Yield: 690 mg (66 % of theory) Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI-): m/z = 432, 434, 436 [M-H]-The following compounds are obtained analogously to Example XXI:
(1) (3,5-dichloro-N-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-phenylsulphonamide O-N
. N
HN
O=s=0 CI I CI
Mass spectrum (ESI+): m/z = 434, 436, 438 [M+H]+
(2) (3,5-dichloro-N-[6-(3-phenyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-phenylsulphonamide O-N
HN
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 496, 498, 500 [M+H]+
(3) ethyl 5-[6-(3,5-dichloro-phenylsulphonylamino)-naphthalen-1-yl]-[1,2,4]oxad iazol e-3-carboxyl ate O
o N
O ~N
O=s=0 CI d CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(4) N-[5-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide N-O "1 N
HN
O=s=O
CI Cl Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
(5) 3,5-dichloro-N-[5-(3-phenoxymethyl -[1, 2,4]oxadiazol-5-yl)-naphthalen-2-yl]-phenylsulphonamide O
N
O iN
Nz~
HN
O=s=O
CI CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 526, 528, 530 [M+H]+
(6) N-[5-(3-phenylsuIphonylm ethyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide O
N~S
0 iN
HN
O=s=0 CI CI
Rf value: 0.70 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 572, 574, 576 [M-H]-(7) ethyl 5-[6-(3,5-dichloro-phenylsulphonylamino)-naphthalen-2-yl]-io [1,2,4]oxadiazole-3-carboxylate o-N 0 J\ N 0--\
HN
O=s=0 CI CI
Rf value: 0.61 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(8) N-[6-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide O-N
HN
O=s=0 CI CI
Rf value: 0.63 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
(9) 3,5-dichloro-N-[6-(3-phenoxymethyl -[1, 2,4]oxadiazol-5-yl)-naphthalen-2-yl]-phenylsulphonamide O-N
J:\ N 0-0 HN
O=s=0 CI & CI
Rf value: 0.78 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 526, 528, 530 [M+H]+
(10) N-[6-(3-phenylsuIphonylm ethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide O-N
N~.0 S' o' HN
O=s=0 CI CI
Rf value: 0.51 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 572, 574, 576 [M-H]-Example XXII
6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl chloride O cl HN
O=S=0 CI Cl Prepared by reacting 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid with thionyl chloride at reflux temperature.
The following compounds are obtained analogously to Example XXII:
(1) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carbonyl chloride n cI
HN
O=s=0 CI I d CI
Example XXIII
3,5-dichloro-N-f6-(5-methyl-f 1.3.41oxadiazol-2-yl)-naphthalen-2-yll-phenylsulphonamide NI _ N0 H N
O=s=0 CI I CI
270 mg N-[6-(N'-acetyl-hydrazinocarbonyl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide are dissolved in 2 ml phosphorus oxychloride and stirred for 3 h at 80 C. Then the mixture is added to ice water, the precipitate formed is suction filtered, washed with water and dried. The crude product is stirred with ethanol, finely suspended in the ultrasound bath, suction filtered, washed with diethyl ether and dried.
Yield: 100 mg (39 % of theory) Rf value: 0.75 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 434, 436, 438 [M+H]+
Example XXIV
N-[6-(N'-acetyl-hydrazinocarbonyl)-naphthalen-2-yll-3,5-dichloro-phenylsulphonamide H
HN'N( O O
HN
O=s=0 \
CI I d CI
A mixture of 500 mg 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carbonyl chloride, 250 mg acetic hydrazide and 3 ml 2,4,6-trimethylpyridine in 3 ml N,N-dimethylformamide is stirred overnight at 80 C. Then the mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid and saturated sodium chloride solution, dried on magnesium sulphate and evaporated 1o down. The residue is purified by chromatography through a silica gel column with methylene chloride/methanol (99:1 to 80:20) as eluant.
Yield: 270 mg (50 % of theory) Rf value: 0.58 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 452, 454, 456 [M+H]+
Example XXV
6-pyrimid in-2-yl-naphthalen-2-ylam ine N~
\ \ \N
Prepared by treating tert. butyl (6-pyrimidin-2-yl-naphthalen-2-yl)-carbamate with trifluoroacetic acid in methylene chloride at ambient temperature.
Rf value: 0.20 (silica gel, petroleum ether/ethyl acetate = 2:1) The following compounds are obtained analogously to Example XXV:
(1) 5-pyrimidin-2-yl-naphthalen-1-ylamine N ~N
Rf value: 0.26 (silica gel, petroleum ether/ethyl acetate = 1:1) Example XXVI
6-tert.-butoxycarbonylamino-naphthalen-2-yl-boric acid OH
O Nz~ LOH
ON
H
8.73 ml n-butyllithium solution (1.6M in hexane) are added dropwise to 1.50 g tert. Butyl (6-bromo-naphthalen-2-yl)-carbamate in 15 ml anhydrous io tetrahydrofuran under an argon atmosphere at -70 C. The suspension is stirred for one hour at -50 C, then 1.61 ml triisopropyl borate, dissolved in ml anhydrous tetrahydrofuran, are added dropwise within 5 minutes. The suspension is slowly heated to ambient temperature, combined with 10 ml 1 N
hydrochloric acid and stirred for 20 minutes at ambient temperature. The aqueous phase is saturated with common salt and the organic phase is separated off. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium hydrogen carbonate solution, dried on magnesium sulphate and evaporated down.
The flask residue is chromatographed through a silica gel column with methylene chloride/methanol (98:2 to 95:5) as eluant.
Yield: 590 mg (44 % of theory) Rf value: 0.42 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 288 [M+H]+
The following compounds are obtained analogously to Example XXVI:
(1) 5-tert.-butoxycarbonylamino-naphthalen-1 -yl-boric acid HO,B,OH
C; 6 OUI NH
Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 288 [M+H]+
(2) 6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-boric acid N-O
>
Pa'- N
HO' B, OH
(carried out with tert.-butyllithium and trimethyl borate) io Example XXVII
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-oxo-4,5-dihydro-[1,2,41oxadiazol-3-yl)-naphthalen-2-yll-amino}-acetate / N
0 ' )=O
O
~ H
N /
O=s=O
CI I / CI
A solution of 400 mg bis-(trichloromethyl)-carbonate in 10 ml methylene chloride is added dropwise at -60 C to 570 mg tert. butyl {(3,5-dichloro-phenylsulphonyl)-[6-(N-hydroxycarbamimidoyl)-naphthalen-2-yl]-amino}-acetate and 0.35 ml triethylamine in 20 ml methylene chloride. After half an hour the cooling bath is removed and the reaction mixture is stirred overnight.
Then the reaction mixture is diluted with ethyl acetate, washed successively with saturated ammonium chloride, sodium hydrogen carbonate and sodium chloride solution, dried on magnesium sulphate and evaporated down. The residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (9:1 to 0:10).
Yield: 480 mg (80 % of theory) Rf value: 0.70 (silica gel, petroleum ether/ethyl acetate = 2:8) Mass spectrum (ESI-): m/z = 548, 550, 552 [M-H]-Tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate washed obtained as a by-product.
/O O N-N
O=s=0 CI I CI
Rf value: 0.85 (silica gel, petroleum ether/ethyl acetate = 2:8) Example XXVIII
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-morpholin-4-ylmethyl-[1,2,41oxadiazol-3-yl)-naphthalen-2-yll-amino}-acetate N
I e N N
OO
N \ \
O=s=0 CI I CI
A mixture of 100 mg tert. butyl [[5-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate, 20 pl morpholine and 29 mg potassium carbonate in 1 ml N,N-dimethylformamide is stirred overnight at ambient temperature. For working up the reaction mixture is diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with petroleum ether/ethyl acetate (1:1) as eluant.
Yield: 73 mg (67 % of theory) Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 633, 635, 637 [M+H]+
Example XXIX
3,5-dichloro-N-[6-(5-methyl-[1,2,41oxadiazol-3-yl)-naphthalen-1-yll-phenylsulphonamide N-O
/ N
HN,S' CI
/I
O
CI
io 160 mg copper(II)acetate and 247 pl triethylamine are added to 405 mg 6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalene-1-boric acid, 200 mg of 3,5-dichloro-phenylsulphonamide and 100 mg molecular sieve (4 A) in 15 ml methylene chloride and the reaction mixture is stirred for 24 h at ambient temperature. Then the mixture is diluted with ethyl acetate, washed with 1 N
sodium hydroxide solution, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography.
Yield: 120 mg (31 % of theory) Example XXX
3-Bromo-5-chloro-phenylsulphonyl chloride CI
0=s=0 Br CI
A solution of 400 mg sodium nitrite in 0.6 ml of water is added dropwise to 1.03 g 3-bromo-5-chloro-aniline in 2 ml concentrated hydrochloric acid while the mixture is cooled in a bath of ice/common salt. The reaction mixture is stirred for 15 minutes at 0 C and then while being cooled it is added to a mixture of 4 ml of a saturated solution of sulphur dioxide in glacial acetic acid (approx. 30 %) and 200 mg copper(II)chloride-dihydrate in 0.4 ml of water.
The cooling bath is removed and the reaction mixture is stirred for 15 minutes at ambient temperature, then in the water bath with gentle heating until no further development of gas can be detected. Some ice water is then added while cooling with an ice bath. After 5 minutes the precipitate formed is suction filtered, washed with some ice water and dried in the desiccator. The sulphonyl chloride obtained is reacted further without any further purification.
Yield: 1.13 mg (78 % of theory) Example XXXI
tert.-butyl 4-(2-aminomethyl -benzoyl)-piperazine-1-carboxylate O
ON UO
I
I
O
Prepared by hydrogenation of tert.-butyl 4-(2-cyanobenzoyl)-1-piperazine-carboxylate in ethanol/chloroform in the presence of platinum dioxide at ambient temperature and at a partial hydrogen pressure of 50 psi.
Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 320 [M+H]+
The following compounds are obtained analogously to Example XXXI:
(1) (2-aminomethyl-phenyl)-morpholin-4-yl-methanone O N
~~~
O
Mass spectrum (ESI+): m/z = 221 [M+H]+
Example XXXII
Benzyl 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylate o o I
HN,' cl cl 1.12 ml ethyldiisopropylamine and 610 mg 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide-hydrochloride are added to 1.05 g 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid and 0.33 ml benzylalcohol in 20 ml acetonitrile and the reaction mixture is stirred for 1.5 h at ambient temperature. Then another 200 mg 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide-hydrochloride are added and the reaction io mixture is stirred overnight at ambient temperature. Then the reaction mixture is evaporated down and the residue is distributed between tert-butylmethylether and dilute citric acid. The organic phase is washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is stirred with a little methanol, suction filtered, washed with a little methanol and dried.
Yield: 389 mg (30 % of theory) Rf value: 0.80 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 484, 486, 488 [M-H]-Example XXXIII
N-(4-aminomethyl-pyridin-2-yl)-N',N'-dimethyl-ethane-l ,2-diamine N N
H
Prepared by treating 2-(2-dimethylamino-ethylamino)-isonicotinonitrile with hydrogen (50 psi) in the presence of Raney nickel in a mixture of methanol and methanolic ammonia solution at ambient temperature.
Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 195 [M+H]+
The following compounds are obtained analogously to Example XXXIII:
(1) N-(4-aminomethyl-pyridin-2-yl)-N,N',N'-trimethyl-ethane-l,2-diamine N NiN~
I
1o Rf value: 0.10 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 209 [M+H]+
(2) N-(5-aminomethyl-pyridin-2-yl)-N,N',N'-trimethyl-ethane-l,2-diamine NHZ
'NI NN
Rf value: 0.15 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 209 [M+H]+
Example XXXIV
2-(2-dimethylamino-ethylamino)-isonicotinonitrile N
II
N NN
H
Prepared by reacting 2-chloro-4-cyano-pyridine with N,N-dimethyl-ethylenediamine in N,N-dimethylformamide in the presence of potassium carbonate at 100 C.
Rf value: 0.30 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 95:5:1) Mass spectrum (ESI+): m/z = 191 [M+H]+
The following compounds are obtained analogously to Example XXXIV:
(1) 2-[(2-dimethylamino-ethyl)-methyl-amino]-isonicotinonitrile N
N N
(The reaction is carried out in dimethylsulphoxide.) Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. Aqueous io ammonia = 95:5:0.1) Mass spectrum (ESI+): m/z = 205 [M+H]+
(2) 6-[(2-dimethylamino-ethyl)-methyl-amino]-nicotinonitrile N
N NN
(The reaction is carried out in dimethylsulphoxide.) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 95:5:0.1) Mass spectrum (ESI+): m/z = 205 [M+H]+
Example XXXV
Tert. Butyl {(3,5-dichloro-phenylsuIphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,21dioxaborolan-2-yl)-naphthalen-2-yll-amino}-acetate o O To B,O
~N
O=s=0 CI \ I CI
A mixture of 396 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)-(6-trifluoro-methanesulphonyloxy-naphthalen-2-yl)-amino]- }-acetate, 269 pl triethylamine and 26 mg [1,1'-bis-(diphenylphosphino)ferrocene]-dichloro-palladium(II) in 4 ml dioxane under an argon atmosphere is combined with the 327 mg of bis-(pinacolato)-diborane and gently refluxed for 5.5 h. After standing overnight at ambient temperature the reaction mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is purified by 1o chromatography through a silica gel column with petroleum ether/ethyl acetate (95:5 to 90:10) as eluant.
Yield: 216 mg (57 % of theory) Rf value: 0.35 (silica gel, methylene chloride) Mass spectrum (ESI+): m/z = 609, 611, 613 [M+NH4]+
The following compounds are obtained analogously to Example XXXV:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate O,B.O
O~N` '~ ci O ,S / I
CI
Rf value: 0.77 (silica gel, methylene chloride) Mass spectrum (ESI+): m/z = 609, 611, 613 [M+NH4]+
Example XXXVI
N-(2-chloro-pyrimidin-4-yl)-N,N',N'-timethyl-ethane-l ,2-diamine N
H
CI\/N N
Prepared by reacting 2,4-dichloropyrimidine with N,N,N'-trimethyl -ethane-l,2-diamine in the presence of diisopropylethylamine in tetrahydrofuran at ambient temperature.
Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 215 [M+H]+
The following compounds are obtained analogously to Example XXXVI:
(1) N'-(2-chloro-pyrimidin-4-yl)-N,N-dimethyl-ethane-1,2-diamine N
CI\ N NH
N
(The reaction takes place in N,N-dimethylformamide in the presence of potassium carbonate.) Mass spectrum (ESI+): m/z = 201 [M+H]+
(2) 4-(6-iodo-pyridazin-3-yl)-morpholine ~o N N
(The reaction takes place with 3,6-diiodopyridazine in dioxane in the presence of potassium carbonate.) Mass spectrum (ESI+): m/z = 292 [M+H]+
(3) N'-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-ethane-1,2-diamine H
NN
N
CI
(The reaction takes place in dimethylsulphoxide in the presence of potassium carbonate.) Example XXXVII
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-4-yl)-naphthalen-1-yll-amino}-acetate o N
O 61 "
CI
io A mixture of 40 mg tert. butyl [[5-(2-chloro-pyrimidin-4-yl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate, 15 pl morpholine and 20 pl diisopropylethylamine in 1 ml isopropanol is heated to 120 C in a microwaveable vessel for 10 minutes. The reaction mixture is evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (85:15) as eluant.
Yield: 28 mg (64 % of theory) Rf value: 0.12 (silica gel, petroleum ether/ethyl acetate = 5:1) The following Examples are obtained analogously to Example XXXVII:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-naphthalen-1-yl]-amino}-acetate CO
N
N N
I /
ON` ~~ YCI
S
O
CI
Rf value: 0.14 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
Example XXXVIII
6-ftert-butoxycarbonylmethyl-(3,5-dichloro-phenylsuIphonyl)-aminol-naphthalene-2-boric acid Y OH
OO B,OH
N
O=s=0 CI
CI
1o Prepared by treating tert. butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthaIen-2-yl]-amino}-acetate with sodium metaperiodate and ammonium acetate in acetone.
Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 527, 529, 531 [M+NH4]+
Example XXXIX
N'-(5-bromo-pyrazin-2-vl)-N, N-dimethvl-ethane-1,2-diamine N
N\ /NH
Br N
13.79 g sodium hydride (60% in mineral oil) are added batchwise to 24.00 g 5-bromo-pyrazin-2-ylamine and 19.87 g (2-chloro-ethyl)-dimethyl-amine-hydrochloride in 300 ml N,N-dimethylformamide at 0 C. After ten minutes the reaction mixture is heated to 80 C for 2 h. After cooling to ambient temperature the reaction mixture is divided between semi-saturated sodium chloride solution and ethyl acetate. The aqueous phase is extracted with io ethyl acetate and the combined organic phases are dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with methylene chloride/methanol (9:1 to 6:4) as eluant. The crude product is taken up in 150 ml of ethyl acetate and stirred with 12 g activated charcoal. After one hour the activated charcoal is filtered off, the filtrate is evaporated down, stirred with some petroleum ether and stored in the freezer for one hour. Then the petroleum ether is decanted off and the solid remaining is dried under a high vacuum.
Yield: 11.00 g (33 % of theory) Mass spectrum (ESI+): m/z = 245, 247 [M+H]+
Example XL
N'-(6-bromo-pyridazin-3-vl)-N, N-dimethvl-ethane-1,2-diamine H
N NN
Br Prepared by treating N'-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-ethane-1,2-diamine with 48% hydrobromic acid at 100 C.
Mass spectrum (ESI+): m/z = 245, 247 [M+H]+
Example XLI
4-(5-bromo-pyrazin-2-yl)-morpholine ('~ o /N
N
~N
Br 3.18 g N-bromosuccinimide are added at 0 C to 2.95 g 4-pyrazin-2-yl-morpholine in 200 ml methylene chloride and the reaction mixture is heated to ambient temperature overnight with stirring. Then another 400 mg N-bromosuccinimide are added while cooling with an ice bath and the reaction mixture is stirred for a further 3 h. For working up the reaction mixture is washed with water and the organic phase is combined with magnesium io sulphate and silica gel, stirred vigorously for 30 minutes and filtered.
The filter cake is washed with a little methylene chloride followed by 200 ml of ethyl acetate. The combined filtrates are evaporated down. The flask residue is suction-filtered with tert.-butylmethyl ether, washed with a little tert.-butylmethylether and dried.
Yield: 3.05 g (69 % of theory) Rf value: 0.65 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 244, 246 [M+H]+
Preparation of the End compounds Example 1 [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-2-yll-(3,5-dichloro-phenyl-suIphonyl)-aminol-acetic acid N
O H
HOTO
N
O=s=0 CI CI
0.40 ml 1 N sodium hydroxide solution are added to 100 mg methyl [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenyl-suIphonyl)-amino]-acetate in 3 ml of methanol and the suspension is stirred io overnight at ambient temperature. For working up 0.40 ml 1 N hydrochloric acid are added dropwise and the mixture is diluted with approx. 15 ml of water. The precipitate formed is suction filtered and washed with water. The crude product is chromatographed through a silica gel column with ethyl acetate/methanol (100:0 to 98:2) as eluant. The product fractions are evaporated down and the flask residue is taken up in dilute sodium hydroxide solution. The product is precipitated by the addition of dilute hydrochloric acid, suction filtered, washed with water and dried.
Yield: 35 mg (36 % of theory) Rf value: 0.35 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
The following compounds are obtained analogously to Example 1:
(1) [(5-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid N
O Z", HO O
N
O=s=0 CI CI
Rf value: 0.58 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(2) [[5-(4-aminomethyl-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid NHZ
H O N
HO O
N
O=s=O
CI CI
Mass spectrum (ESI+): m/z = 572, 574, 576 [M+H]+
(3) [(3,5-dichloro-phenylsulphonyl)-(6-phenylaminocarbonyl-naphthalen-2-yl)-amino]-acetic acid o ~
HO O N I
~N H
0=s=0 Cl CI
Rf value: 0.25 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(4) [(3,5-dichloro-phenylsulphonyl)-(6-m ethyl aminocarbonyl-naphthalen-2-yl)-amino]-acetic acid O
HO CO H O O X A N
N I A ~ H
O=s=0 CI I CI
Rf value: 0.28 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 467, 469, 471 [M+H]+
(5) [(3,5-dichloro-phenylsulphonyl)-(4-methoxy-naphthalen-2-yl)-amino]-acetic acid HO O '-(' N I
O=s=O
CI I CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 440, 442, 444 [M+H]+
(6) [(5-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H
O N O
I
O
HO CI
, O
CI
Rf value: 0.58 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(7) [(3,5-dichloro-phenylsulphonyl)-(5-m ethyl aminocarbonyl-naphtha len-1-yl)-amino]-acetic acid H
O N", O
HO CI
O
CI
Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 467, 469, 471 [M+H]+
(8) 4-[({5-[carboxymethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalen-1-ylcarbonyl}-amino)-methyl]-benzoic acid H / I OH
O N
O
HO~N O ci O S /
CI
Rf value: 0.30 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 587, 589, 591 [M+H]+
Example 2 [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yll-(3,5-dichloro-phenylsulphonyl)-aminol-acetic acid NHZ
H O N
HO O
N
O=s=O
ciJ CI
A mixture of 200 mg methyl [[5-(4-carbamimidoyl-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate hydrochloride, 500 mg sodium carbonate, 2.5 ml of water and 5 ml of methanol is stirred overnight at ambient temperature and then refluxed for 8 h. After cooling to ambient temperature 1 ml of 1 N sodium hydroxide solution is added. The reaction mixture is stirred overnight at ambient temperature, diluted with some water and acidified with 2N hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried. The crude product thus obtained is stirred with methanol, suction filtered, washed 1o with methanol and ether and dried.
Yield: 90 mg (49 % of theory) Rf value: 0.30 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
Example 3 [(3,5-dichloro-phenylsuIphonyl)-(5-m ethyl am inocarbonyl-naphthalen-2-yl)-aminol-acetic acid H
O N
HO O
N I
O=s=0 CI I CI
10 ml trifluoroacetic acid are added to 3.66 g tert. butyl [(3,5-dichloro-phenylsulphonyl)-(5-methyl aminocarbonyl-naphthalen-2-yl)-amino]-acetate in 50 ml methylene chloride and the reaction mixture is stirred for 4.5 h at ambient temperature. Then the reaction mixture is evaporated down using the rotary evaporator and the flask residue is dissolved with dilute sodium hydroxide solution. This aqueous solution is washed with a little methylene chloride and acidified with 1 N hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried in the desiccator.
Yield: 3.04 g (Yield: 93% of theory) Rf value: 0.30 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI-): m/z = 465, 467, 469 [M-H]-The following compounds are obtained analogously to Example 3:
(1) [[5-(cyclohexylmethyl-aminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O NiD
HO O
N
O=s=0 CI I CI
Rf value: 0.75 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 549, 551, 553 [M+H]+
(2) [(3,5-dichloro-phenylsulphonyl)-(5-phenylaminocarbonyl-naphthalen-2-yl)-amino]-acetic acid H
O N ~
HO O I
N
O=s=0 CI I CI
Rf value: 0.63 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(3) {(3,5-dichloro-phenylsulphonyl)-[5-(3,4-dihydro-1 H-isoquinoline-2-carbonyl)-naphthalen-2-yl]-amino}-acetic acid O
HO O
N
O=s=0 CI CI
Rf value: 0.82 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 569, 571, 573 [M+H]+
(4) [(3,5-dichloro-phenylsulphonyl)-(5-phenylethylaminocarbonyl-naphthalen-2-yl)-amino]-acetic acid H
O N
HO O N
N
O=s=0 CI CI
Rf value: 0.75 (silica gel, methylene chloride/methanol/conc. Aqueous 1o ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(5) [[5-(N-benzyl-N-methyl-aminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid I
O N () HO O
N
O=s=0 Cl CI
Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(6) [(6-aminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O
N
O=s=0 CI CI
Rf value: 0.34 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI+): m/z = 453, 455, 457 [M+H]+
io (7) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl -[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid HO, O AN /
N
O=s=O
CI CI
Rf value: 0.10 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(8) [(3,5-dichloro-phenylsulphonyl)-(6-oxazol-2-yl-naphthalen-2-yl)-amino]-acetic acid HO O N
N
O=s=O
CI CI
Rf value: 0.10 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 475, 477, 479 [M-H]-(9) [(3,5-dichloro-phenylsulphonyl)-naphthalen-1-yl-amino]-acetic acid c YCI
CI
Rf value: 0.20 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 408, 410, 412 [M-H]-io (10) [(6-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O
HO O : /e N~
N I H
0=s=0 CI I & CI
Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(11) {(3,5-dichloro-phenylsulphonyl))-[5-(pyrrolidine-1-carbonyl)-naphthalen-2-yl]-amino}-acetic acid O N'D
HoTO
N
0=s=0 CI CI
Mass spectrum (ESI+): m/z = 507, 509, 511 [M+H]+
(12) [(3,5-dichloro-phenylsulphonyl)-(5-isopropylaminocarbonyl-naphthalen-2-yl)-amino]-acetic acid H
O N`r HOTO
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 495, 497, 499 [M+H]+
(13) [(5-aminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid HO O
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 470, 472, 474[M+NH4]+
io (14) {(3,5-dichloro-phenylsulphonyl)-[5-(2-hydroxy-ethylaminocarbonyl)-naphthalen-2-yl]-amino}-acetic acid H
Ho TO
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 497, 499, 501 [M+H]+
(15) [(5-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dimethyl-phenylsulphonyl)-amino]-acetic acid O N I
HOTO
N I
O=s=0 Jta"
Rf value: 0.15 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 503 [M+H]+
(16) [(6-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dimethyl-phenylsulphonyl)-amino]-acetic acid O
HO O N
N H
O=s=0 Rf value: 0.28 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 503 [M+H]+
(17) [(7-benzoylamino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H N N
O=s=0 H
CI I CI
Mass spectrum (ESI-): m/z = 527, 529, 531 [M-H]-(18) [{7-[(4-chloro-pyridin-2-carbonyl)-amino]-naphthalen-2-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid HO f I / /
N CI
H I
O=S=O N
CI CI
Mass spectrum (ESI-): m/z = 562, 564, 566, 568 [M-H]-(19) [[7-(3-benzyl-ureido)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid HOf I 0 N 14- 1-:11 NAN
O=S=O H H
CI CI
Mass spectrum (ESI-): m/z = 556, 558, 560 [M-H]-(20) [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-3-yl-naphthalen-2-yl)-amino]-io acetic acid N
T I
N
O=S=0 Cl CI
Rf value: 0.55 (silica gel, ethyl acetate/acetic acid = 99:1) Mass spectrum (ESI+): m/z = 487, 489, 491 [M+H]+
(21) {(3,5-dichloro-phenylsulphonyl)-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid HO
N
O=S=0 Nom( CI CI
Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(22) {(3,5-dichloro-phenylsuIphonyl)-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid o-'~
N N N
HO O
N
O=s=0 CI CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(23) {(3,5-dichloro-phenylsuIphonyl)-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid N--~
0 ,N
HO O C~
N
O=s=0 CI CI
Rf value: 0.30 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(24) {(3,5-dichloro-phenylsuIphonyl)-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O-N~
Ho TO N
N
O=s=0 CI Cl Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(25) {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O-N
HO O ~N
N
O=s=0 CI I CI
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 554, 556, 558 [M+H]+
(26) {(3,5-dichloro-phenylsulphonyl)-[5-(5-phenyl-[1,2,4]oxadiazol-3-yl)-io naphthalen-2-yl]-amino}-acetic acid oP
N N N
HOTO
N
O=s=O
CI I CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 554, 556, 558 [M+H]+
(27) {(3,5-dichloro-phenylsulphonyl)-[5-(5-benzyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid N N N
HOTO
N I
O=s=0 CI CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(28) {(3,5-dichloro-phenylsulphonyl)-[5-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid N N N
HOTO
N I
O=s=0 CI Cl Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 520, 522, 524 [M+H]+
(29) {(3,5-dichloro-phenylsulphonyl)-[6-(5-phenyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid N-O _ HO O jCOA N /
N
0=s=0 CI CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 554, 556, 558 [M+H]+
(30) {(3,5-dichloro-phenylsulphonyl)-[6-(5-phenyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid HO O
N
N
O=s=O
CI CI
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(31) {(3,5-dichloro-phenylsulphonyl)-[6-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid H O O I
CON
N
O=s=0 CI CI
1o Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 520, 522, 524 [M+H]+
(32) {(3,5-dichloro-phenylsulphonyl)-[5-(5-hydroxy-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid OH
O
NN N
HO O
N
O=s=0 CI CI
Rf value: 0.30 (silica gel, methylene chloride/methanol/acetic acid = 5:1:0.1) Mass spectrum (ESI+): m/z = 494, 496, 498 [M+H]+
(33) {(3,5-dichloro-phenylsulphonyl)-[5-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid cI
cI
o cI
N
HOTO
N
O=s=0 CI CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 594, 596, 598, 600 [M+H]+
(34) {(3,5-dichloro-phenylsulphonyl)-[5-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O
N o 0 ,N
Ho o N
O=s=0 CI d CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) io Mass spectrum (ESI+): m/z = 550, 552, 554 [M+H]+
(35) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1.3.4]oxadiazol-2-yl)-naphthalen-2-yl]-amino}-acetic acid N-N
HO ~
,O IDCJ--,- 0 N
O=s=0 CI CI
Rf value: 0.26 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(36) {(3,5-dichloro-phenylsulphonyl)-[5-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid N-O ,N
HOTO
N I ~
O=s=O
CI I & CI
Rf value: 0.60 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(37) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyloxymethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid N--( -0 O N
HO O N~
N
O=s=O
CI I CI
Rf value: 0.70 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESI-): m/z = 582, 584, 586 [M-H]-(38) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenylsulphonylmethyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid N
0 iN
HO 0 i N
O=s=0 CI I CI
Rf value: 0.50 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESI-): m/z = 630, 632, 634 [M-H]-(39) [(5-benzoylamino-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid HN
I C;) 0 ~N`S 0 HO CI
6' f CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 527, 529, 531 [M-H]-(40) [(3,5-dichloro-phenylsulphonyl)-(5-phenylacetylamino-naphthalen-1-yl)-amino]-acetic acid HN
HO CI
S I
O
Cl Rf value: 0.32 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 541, 543, 545 [M-H]-(41) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-prop ionylamino)-naphthalen-1-yl]-amino}-acetic acid O
HN
I C;) 0 O
)LI-IN` O CI
HO S
O
CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 555, 557, 559 [M-H]-(42) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-ureido)-naphthalen-1-yl]-amino}-acetic acid HN NJO
H
I
O
HO CI
O
CI
Rf value: 0.28 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 542, 544, 546 [M-H]-(43) [[5-(3-benzyl-ureido)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O
HNN II \~
O
HO CI
O
CI
Rf value: 0.26 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 556, 558, 560 [M-H]-(44) [{5-[(4-chloro-pyridin-2-yl-carbonyl)-amino]-naphthalen-1-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid N
HN
CI
HO CI
O
CI
Rf value: 0.45 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 564, 566, 568 [M+H]+
(45) [(3,5-dichloro-phenylsulphonyl)-(5-phenylaminocarbonyl-naphthalen-1-yl)-amino]-acetic acid H
O cC
N` O
HO S CI
O I
CI
Rf value: 0.17 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(46) [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-4-yl-naphthalen-2-yl)-amino]-acetic acid N
HO O I I
N
O=s=O
CI I CI
Rf value: 0.60 (silica gel, ethyl acetate/acetic acid = 99:1) Mass spectrum (ESI+): m/z = 487, 489, 491 [M+H]+
(47) [(3,5-dichloro-phenylsulphonyl)-(6-furan-3-yl-naphthalen-2-yl)-amino]-acetic acid HO O O Nz~ N
o=s=o CI CI
Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate/acetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 474, 476, 478 [M-H]-(48) {(3,5-dichloro-phenylsulphonyl)-[6-(3,5-dimethyl-isoxazol-4-yl)-naphthalen-2-yl]-amino}-acetic acid ,N
HO O I O
N / /
o=s=o CI CI
Rf value: 0.57 (silica gel, cyclohexane/ethyl acetate/acetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 503, 505, 507 [M-H]-(49) {(3,5-dichloro-phenylsulphonyl)-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetic acid O_~
N N
O
HON 0 O / Ycl CI
Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(50) [(3,5-dichloro-phenylsulphonyl)-(6-furan-2-yl-naphthalen-2-yl)-amino]-acetic acid HO 0 I 0 Nz~ N
O=s=0 CI CI
Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate/acetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 474, 476, 478 [M-H]-(51) [(5-aminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid I
O
N- , HO ICI
CI
Rf value: 0.52 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 453, 455, 457 [M+H]+
H I
y O N NN
N
O=s=0 CI
Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 700, 702, 704 [M+H]+
15 (49) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-({6-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-3-ylmethyl}-aminocarbonyl)-naphthalen-2-yl]-amino}-acetate / N
y O N N
O O
N
O=s=0 ciJ CI
Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 700, 702, 704 [M+H]+
(50) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-carbamoyl}-naphthaIen-2-yl)-amino]-acetate / N I
H
O N NN
/XI O~O H
N
O=s=0 Cl CI
Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. Aqueous io ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 686, 688, 690 [M+H]+
Example VI
6-ftert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-aminol-naphthalene-1-carboxylic acid Y O OH
O ~O
N
O=s=0 CI CI
350 mg benzyl 6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-1-carboxylate are hydrogenated in 25 ml of tetrahydrofuran in the presence of 40 mg palladium on activated charcoal (10 %) at ambient temperature and at a partial hydrogen pressure of 0.38 bar for 4.5 h. Then the catalyst is filtered off and the filtrate is evaporated down.
The flask residue is dissolved slightly with a little tert-butylmethyl ether, diluted with petroleum ether, stirred, suction filtered, washed with petroleum ether and dried.
Yield: 291 mg (96 % of theory) io Rf value: 0.30 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 527, 529, 531 [M+NH4]+
The following compounds are obtained analogously to Example VI:
(1) 5-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsuIphonyl)-amino]-naphthalene-1-carboxylic acid O OH
I
KIN-9, CI
OS
CI
Rf value: 0.25 (silica gel, methylene chloride/methanol = 98:2) Mass spectrum (ESI+): m/z = 527, 529, 531 [M+NH4]+
Example VII
Benzyl 6-amino-naphthalene-1-carboxylate O O I
1.00 g 6-aminonaphthoic acid is suspended in benzylalcohol, combined with 920 mg anhydrous p-toluenesulphonic acid and stirred for a few minutes in the oil bath at 80 C. Then 1.23 g p-toluenesulphonic acid chloride are added and the reaction mixture is stirred for 4 h at 80 C.
A further 600 mg p-toluenesulphonic acid chloride are added and the reaction mixture is stirred for a further 5 h at 80 -90 C. After cooling to ambient temperature the reaction mixture is diluted with 90 ml tert.-butyl methyl ether, the precipitate formed is suction filtered and washed with a little tert.-butylmethylether. The filter cake is taken up in tert.-butyl methyl ether and washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down.
io Yield: 242 mg (16 % of theory) Rf value: 0.85 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 278 [M+H]+
Example VIII
6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid amide HN
O=s=0 CI I d CI
A mixture of 10.00 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid, 24.30 g ammonium carbonate, 8.10 g O-(benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium-tetrafluoroborate and 3.52 ml triethylamine in 120 ml of tetrahydrofuran is stirred overnight at ambient temperature. For working up the reaction mixture is diluted with 150 ml of ethyl acetate and washed with 10 % citric acid solution, 1 N sodium hydroxide solution and saturated sodium chloride solution. The organic phase is dried on magnesium sulphate and evaporated down. The flask residue is stirred with diisopropylether, suction filtered and dried at 40 C in the circulating air dryer.
The sodium hydroxide solution phase is extracted with methylene chloride, during which time a precipitate is formed which is suction filtered and also dried in the circulating air dryer.
Yield: 7.13 g (72 % of theory) Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 393, 395, 397 [M-H]-The following compounds are obtained analogously to Example VIII:
(1) tert. Butyl [(5-aminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate O O
N
O=s=0 CI CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) (2) 7-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid amide HN-'~ O
O=S=O NH2 CI CI
Mass spectrum (ESI+): m/z = 395, 397, 399 [M+H]+
Example IX
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,41oxadiazol-3-yl)-naphthalen-2-yll-amino}-acetate X N-O
O I '-N
O=s=0 CI I Cl A mixture of 400 mg tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(N-hydroxy-carbamimidoyl)-naphthalen-2-yl]-amino}-acetate and 0.16 ml acetic anhydride in 5 ml acetonitrile is heated for five minutes in the microwave at 180 C. The reaction mixture is evaporated down, and the crude product is purified by chromatography through a silica gel column with cyclohexane/ethyl acetate (75:25 to 50:50) as eluant.
Yield: 250 mg (60 % of theory) Rf value: 0.90 (silica gel, cyclohexane/ethyl acetate = 1:1) The following compounds are obtained analogously to Example IX:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[7-(5-methyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate O
N I/ O~N.
O
0=s=0 Nom( ciJ CI
Mass spectrum (ESI+): m/z = 565, 567, 569 [M+NH4]+
(2) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-methyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate 0-~
NN N
O=s=0 CI CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 565, 567, 569 [M+NH4]+
(3) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-phenyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate OP
NN N
O O
O=s=0 ciJ CI
(reaction carried out with benzoyl chloride in 2,4,6-trimethylpyridine) Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 610, 612, 614 [M+H]+
(4) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-benzyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate O \ /
NN N
O O
O=s=0 CI I Cl io (reaction carried out with phenylacetyl chloride in 2,4,6-trimethylpyridine) Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(5) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate o~
NN N
N
O=s=0 CI CI
(reaction carried out with isobutyric acid chloride in 2,4,6-trimethylpyridine) Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 576, 578, 580 [M+H]+
(6) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-phenyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate Y N-O
N
0=s=0 (reaction carried out with benzoyl chloride in 2,4,6-trimethylpyridine and io methylene chloride) Rf value: 0.76 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 610, 612, 614 [M+H]+
(7) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-phenyl-[1,2,4]oxadiazol-yl)-naphthalen-2-yl]-amino}-acetate Y N,0 N
O=s=0 Cl CI
(reaction carried out with phenylacetyl chloride in 2,4,6-trimethylpyridine and methylene chloride) Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 624, 626, 628 [M+H]+
(8) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate N-O
Y I
O 0 ~
N
CIC
N
O=s=0 CI J CI
(reaction carried out with isobutyric acid chloride in 2,4,6-trimethylpyridine and methylene chloride) 1o Rf value: 0.71 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 576, 578, 580 [M+H]+
(9) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-hydroxy-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate OH
0-~
NN N
N
O=s=O
CI CI
(formed as a by-product of the reaction with trichloroacetic acid chloride in 2,4,6-trimethylpyridine) Rf value: 0.30 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESI-): m/z = 548, 550, 552 [M-H]-(10) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate cI
cI
O i cI
N~ N
O O ~ --.:
N I / /
O=s=0 CI I / CI
(reaction carried out with trichloroacetic acid chloride in 2,4,6-tri methyl pyridine) Rf value: 0.70 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 667, 669, 671, 673 [M+NH4]+
(11) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetate o-/
N N
c O Os / q CI
1o Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 565, 567, 569 [M+NH4]+
(12) tert. Butyl [[5-(5-chloromethyl -[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate O-ccI
N N
O O
N \ \
O=s=0 CI
CI
(reaction carried out with chloroacetyl chloride in 2,4,6-trimethylpyridine and methylene chloride) Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 3:1) (13) 3-(5-bromo-naphthalen-2-yl)-5-methyl-[1,2,4]oxadiazole N-O
C;)O Al N i>-Br Rf value: 0.74 (silica gel, cyclohexane/ethyl acetate = 1:1) (14) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetate N
I
O
0-N (N`g' CI
O
CI
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 548, 550, 52 [M+H]+
Example X
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(N-hydroxycarbamimidoyl)-naphthalen-2-yll-amino}-acetate N.OH
NHZ
O O J:/ OI
N
O=s=0 CI CI
A mixture of 2.46 g tert. butyl [(6-cyano-naphthalen-2-yl)-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate, 750 mg hydroxylamine-hydrochloride and 1.58 ml triethylamine in 25 ml absolute ethanol is refluxed for 3 h. The precipitate formed is suction filtered, washed with diethyl ether and dried at 50 C in the circulating air dryer.
Yield: 1.57 g (60 % of theory) Rf value: 0.10 (silica gel, cyclohexane/ethyl acetate = 3:1) The following compounds are obtained analogously to Example X:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[7-(N-hydroxycarbamimidoyl)-naaphhthalen-2-yl]-amino}-acetate O
N N.OH
O=S=O NHZ
CI I CI
(2) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(N-hydroxycarbamimidoyl)-naphthalen-2-yl]-amino}-acetate OH
~ N NHZ
/O O
N
O=s=0 ciJ CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 524, 526, 528 [M+H]+
(3) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(N-hydroxycarbamimidoyl)-naphthalen-1-yl]-amino}-acetate OH
O~` ~ YCI
CI
Rf value: 0.38 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 524, 526, 528 [M+H]+
(4) [(5-aminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid CI
Rf value: 0.25 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 509, 511, 513 [M+H]+
(5) 5-bromo-N-hydroxy-naphthalene-2-carboxamidine N
I
PCYII~ NH2 Br Rf value: 0.54 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 265, 267 [M+H]+
(6) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[2-(N-hydroxycarbamimidoyl)-naphthalen-1-yl]-amino}-acetate I O
HO_N (N ;S' CI
O
CI
Rf value: 0.42 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 524, 526, 528 [M+H]+
Example XI
3,5-dichloro-N-(6-cyano-naphthalen-2-yl)-phenylsulphonamide N
H N I D
O=S=0 CI CI
1.48 ml trifluoroacetic anhydride are added dropwise to 3.43 g 6-(3,5-io dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid amide and 3.64 ml triethylamine in 130 ml methylene chloride while cooling with an ice bath. The reaction mixture is stirred for 3 h at ambient temperature, then another 1.48 ml trifluoroacetic anhydride are added dropwise while cooling with an ice bath. After another two hours at ambient temperature a further 1.48 ml trifluoroacetic anhydride are added and the reaction mixture is stirred overnight at ambient temperature. For working up the reaction mixture is combined with 70 ml of water. The organic phase is separated off, washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (75:25 to 50:50) as eluant.
Yield: 2.29 g (70 % of theory) Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESI-): m/z = 375, 377, 379 [M-H]-The following compounds are obtained analogously to Example XI:
(1) 3,5-dichloro-N-(7-cyano-naphthalen-2-yl)-phenylsulphonamide H N J
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 394, 396, 398 [M+NH4]+
(2) 3,5-dichloro-N-(5-cyano-naphthalen-2-yl)-phenylsulphonamide N
II
HN / /
O=s=0 CI I / CI
Rf value: 0.68 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 375, 377, 379 [M-H]-(3) 3,5-dichloro-N-(5-cyano-naphthalen-1-yl)-phenylsulphonamide N
II
HN.. " Cl /I
CI
Rf value: 0.86 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 375, 377, 379 [M-H]-Example XII
tert. Butyl [(3,5-dichloro-phenvlsulphonvl)-(6-oxazol-2-yl-naphthalen-2-yl)-aminol-acetate N
O
O=s=0 ciJ CI
A mixture of 1.43 g tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(2-oxo-ethyl-aminocarbonyl)-naphthalen-2-yl]-amino}-acetate and 620 mg Burgess reagent in 10 ml of tetrahydrofuran is heated to 170 C in the microwave for 5 min. The reaction mixture is evaporated down and chromatographed through io a silica gel column with cyclohexane/ethyl acetate (80:20 to 66:34) as eluant.
Yield: 179 mg (13 % of theory) Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 3:1) Example XIII
tert. Butyl {(3,5-dichloro-phenvlsulphonvl)-[6-(2-oxo-ethylaminocarbonyl)-naphthalen-2-yll-amino}-acetate N I / / H
O=s=0 CI CI
Prepared by oxidation of tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(2-2o hydroxy-ethylaminocarbonyl)-naphthalen-2-yl]-amino}-acetate with Dess-Martin reagent in methylene chloride at ambient temperature.
Rf value: 0.70 (silica gel, ethyl acetate) Example XIV
6-[tert.-butoxycarbonylmethyl-(3,5-dichloro-phenylsuIphonyl)-aminol-naphthalene-1-carboxylic acid X O OH
O fO
N
O=s=0 CI CI
0.64 ml trimethylsilyl chloride are added to 1.00 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid and 0.86 ml diisopropylethylamine in 10 ml of tetrahydrofuran while cooling with an ice bath. After ten minutes 2.10 g potassium-bis(trimethylsilyl)-amide are added io batchwise, and the reaction mixture is heated to ambient temperature. After 6 h at this temperature the reaction mixture is combined with 0.20 ml tert.
Butyl bromoacetate and stirred for a further 2 h at ambient temperature. For working up the reaction mixture is combined with 0.44 ml piperazine and 2 ml of methanol. After ten minutes 100 ml 1 N hydrochloric acid are added and the mixture is extracted with ethyl acetate. The organic phase is separated off, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/methanol (20:1 to 10:1) as eluant.
Yield: 730 mg (57 % of theory) Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1) Example XV
N-[7-(3,5-dichloro-phenylsulphonylamino)-naphthalen-2-yll-benzamide HN / / N H
CI CI
104 pl benzoyl chloride are added to 300 mg N-(7-amino-naphthalen-2-yl)-3,5-dichloro-phenylsulphonamide and 0.17 ml triethylamine in 5 ml methylene chloride while cooling with an ice bath. After heating to ambient temperature the reaction mixture is stirred for another 3 h. Then it is combined with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with dilute hydrochloric acid and saturated sodium hydrogen carbonate solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column.
Yield: 310 mg (81 % of theory) io Mass spectrum (ESI-): m/z = 469, 471, 473 [M-H]-The following compounds are obtained analogously to Example XV:
(1) tert. Butyl [{7-[(4-chloro-pyridine-2-carbonyl)-amino]-naphthalen-2-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N CI
N H
0=s=0 N
(2) tert. Butyl [(5-benzoylamino-naphthalen-1 -yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate HN
O
Rf value: 0.54 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI-): m/z = 583, 585, 587 [M-H]-(3) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(5-phenylacetylamino-naphthalen-1-yl)-amino]-acetate /
HN
O
AO CI
CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI-): m/z = 597, 599, 601 [M-H]-(4) tert. Butyl {(3,5-dichloro-phenylsuIphonyl)-[5-(3-phenyl-prop ionylamino)-naphthalen-1-yl]-amino}-acetate O
HN
AO
~N` O CI
O
O s / I
CI
Rf value: 0.34 (silica gel, petroleum ether/ethyl acetate = 2:1) io Mass spectrum (ESI-): m/z = 611, 613, 615 [M-H]-(5) tert. Butyl [{5-[(4-chloro-pyridin-2-yl-carbonyl)-amino]-naphthalen-1-yl}-(3,5-dichloro-phenylsuIphonyl)-amino]-acetate N
HN
CI
O
CI
Rf value: 0.64 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 620, 622, 624 [M+H]+
Example XVI
tert. Butyl [[7-(3-benzyl-ureido)-naphthalen-2-yll-(3,5-dichloro-phenylsulphonyl)-aminol-acetate NJ= N
0=s=0 H H
CI J CI
2 mg 4-dimethylaminopyridine and 18.5 pl benzylisocyanate are added to 60 mg tert. Butyl [(7-amino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetate in 4 ml methylene chloride. The reaction mixture is stirred overnight at ambient temperature and then evaporated down in vacuo. The 1o crude product is purified by chromatography through a silica gel column.
Yield: 74 mg (97 % of theory) Mass spectrum (ESI-): m/z = 658, 660, 662 [M+HCOO]-The following compounds are obtained analogously to Example XVI:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-ureido)-naphthalen-1-yl]-amino}-acetate HN N
H
O
CI
Rf value: 0.78 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(2) tert. Butyl [[5-(3-benzyl-ureido)-naphthalen-1 -yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate O
HN N
A
I~ \
H
~N` O ci O S /
O
CI
Rf value: 0.65 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
Example XVII
tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-3-yl-naphthalen-2-vl)-aminol-acetate N
N
O=s=0 A mixture of 200 mg tert. butyl [(3,5-dichlorophenylsulphonyl)-(6-trifluoromethanesuIphonyloxy-naphthalen-2-yl)-amino]-acetate, 56 mg 3-pyridylboric acid and 69 mg sodium carbonate in 7 ml of toluene is combined with 0.80 ml of ethanol and 0.80 ml of water. The resulting solution is briefly evacuated twice and ventilated with argon. Then 56 mg of tetrakis-(triphenylphosphine)-palladium are added and the mixture is again evacuated and ventilated with argon. The reaction mixture is stirred for 7 h at 83 C and then slowly cooled overnight to ambient temperature. For working up the reaction mixture is mixed with water and extracted with ethyl acetate.
The organic phase is washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with petroleum ether/ethyl acetate (8:2 to 7:3).
Yield: 97 mg (55 % of theory) Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
The following compounds are obtained analogously to Example XVII:
(1) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-4-yl-naphthalen-2-yl)-amino]-acetate N
I
O O
O=s=0 (The reaction is carried out with pinacolyl 4-pyridinylborate.) 1o Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(2) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-furan-3-yl-naphthalen-2-yl)-amino]-acetate O o o N
O=s=0 ciJ CI
Rf value: 0.65 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESI+): m/z = 549, 551, 553 [M+NH4]+
(3) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(3,5-dimethyl-isoxazol-4-yl)-2o naphthalen-2-yl]-amino}-acetate ,N
O
O=s=0 CI CI
Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESI+): m/z = 578, 580, 582 [M+NH4]+
(4) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-furan-2-yl-naphthalen-2-yl)-amino]-acetate N
O=s=0 ciJ CI
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESI+): m/z = 549, 551, 553 [M+NH4]+
(5) tert. Butyl (6-pyrimidin-2-yl-naphthalen-2-yl)-carbamate N
II O N
O I N
H
(The reaction takes place between 4-bromopyridine and 6-tert.-butoxycarbonyl amino-naphthalen-2-yl-boric acid in a mixture of 1,4-dioxane and methanol.) Rf value: 0.63 (silica gel, petroleum ether/ethyl acetate = 1:1) (6) tert. Butyl (5-pyrimidin-2-yl-naphthalen-1-yl)-carbamate N ~N
\\/ONH
TI O
(The reaction takes place between 4-bromopyridine and 5-tert.-butoxycarbonylamino-naphthalen-1-yl-boric acid in a mixture of 1,4-dioxane and methanol.) Rf value: 0.38 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 322 [M+H]+
(7) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-2-yl-naphthalen-2-yl)-amino]-acetate X /
O O
N
N
O=s=0 CI I / CI
(The reaction takes place with diisopropyl 2-pyridinylborate.) Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(8) tert.-butyl 4-(2-{6-[tert.-butoxycarbonylmethyl -(3,5-dichloro-phenylsulphonyl)-amino]-naphthalen-2-yl}-pyrimidin-4-yl)-piperazine-1-carboxylate N
N 3yO
O=s=0 0 ciJ CI
(The reaction takes place between tert.-butyl 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylate and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 728, 730, 732 [M+H]+
(9) tert.-butyl 4-(2-{5-[tert-butoxycarbonylm ethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalen-1-yl}-pyrimidin-4-yl)-piperazine-1-carboxylate rN~O
NJ
N ~N
N` O CI
O OS
CI
(The reaction takes place between tert.-butyl 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylate and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate.) Rf value: 0.65 (silica gel, tert.-butylmethylether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 728, 730, 732 [M+H]+
(10) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(2-morpholin-4-yl-pyrimidin-4-yl)-naphthalen-2-yl]-amino}-acetate O 0 icr(1c N
O=s=0 CI I CI
(The reaction takes place between 4-(4-chloro-pyrimidin-2-yl)-morpholine and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.65 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(11) tert. Butyl [(3,5-dichloro-phenylsulphonyl)-(6-{4-[N-(2-dimethylamino-ethyl)-N-methyl-amino]-pyrimidin-2-yl}-naphthalen-2-yl)-amino]-acetate N
Y
N \
O=s=0 N
ciJ CI
(The reaction takes place between N-(2-chloro-pyrimidin-4-yl)-N,N',N'-io trimethyl -ethane-1,2-diamine and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborol an-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.35 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 95:5:0.1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(12) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-1-yl]-amino}-acetate ~o NJ
N ~N
O
~N, 1O CI
O OS / I
CI
(The reaction takes place between 4-(2-chloro-pyrimidin-4-yl)-morpholine and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate.) Rf value: 0.22 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(13) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{6-[4-(2-dimethylamino-ethyl amino)-pyrimidin-2-yl]-naphtha len-2-yl}-amino)-acetate Y N
OTO ~N NH
N
O=s=0 N
ciJ CI
(The reaction takes place between N'-(2-chloro-pyrimidin-4-yl)-N,N-dimethyl-ethane-1,2-diamine and tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-io (4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.28 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) (14) tert. Butyl [[5-(2-chloro-pyrimidin-4-yl)-naphthalen-1 -yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate N I CI
SIN
O
O N, 1~ CI
S/
CI
(The reaction takes place between 2,4-dichloropyrimidine and tert. Butyl {(3,5-d ich loro-ph enylsu l phonyl)-[5-(4,4,5,5-tetramethyl-[1 ,3,2]d ioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate.) Rf value: 0.13 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 578, 580, 582 [M+H]+
(15) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(6-morpholin-4-yl-pyridazin-3-yl)-naphthalen-2-yl]-amino}-acetate rO
N NI-) OO
N
O=s=0 ciJ CI
(The reaction takes place between 4-(6-iodo-pyridazin-3-yl)-morpholine and 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-2-boric acid.) Rf value: 0.63 (silica gel, methylene chloride/methanol = 95:5) (16) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-io 5-yl)-naphthalen-1-yl]-amino}-acetate cI
N" N
I , P'O O ~ . 'CI
S
CI
Mass spectrum (ESI+): m/z = 578, 580, 582 [M+H]+
(The reaction takes place between 5-bromo-2-chloro-pyrimidine and tert.
Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate.) (17) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{6-[5-(2-dimethylamino-ethylamino)-pyrazin-2-yl]-naphtha len-2-yl}-amino)-acetate H
NYN
Y I
O N
O=s=0 ciJ CI
(The reaction takes place between N'-(5-bromo-pyrazin-2-yl)-N,N-dimethyl-ethane-1,2-diamine and 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-2-boric acid.) Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
io (18) tert. Butyl ((3,5-dichloro-phenylsulphonyl)-{6-[6-(2-dimethylamino-ethylamino)-pyridazin-3-yl]-naphtha len-2-yl}-amino)-acetate H
N N N
OO
N
O=s=0 ciJ Cl (The reaction takes place between N'-(6-bromo-pyridazin-3-yl)-N,N-dimethyl-ethane-1,2-diamine and 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenyl-sulphonyl)-amino]-naphthalene-2-boric acid.) Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) (19) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetate N
00 ~N
N \ \
O=s=0 ciJ CI
(The reaction takes place between 4-(2-chloro-4-pyrimidinyl)-morpholine and tert. butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-amino}-acetate.) Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
(20) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-morpholin-4-yl-pyrazin-yl)-naphthalen-2-yl]-amino}-acetate ro /N
N I
N \ \
O=s=0 ciJ CI
(The reaction takes place between 4-(5-bromo-pyrazin-2-yl)-morpholine and 6-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalene-2-boric acid.) Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
Example XVIII
3,5-dichloro-N-(6-trifluoromethanesulphonyloxy-naphthalen-2-yl)-phenylsulphonamide HN / / O F F
O=s=0 CI I / CI
A solution of 0.36 ml trifluoromethanesulphonic acid anhydride in 5 ml methylene chloride is added dropwise to 760 mg of 3,5-dichloro-N-(6-hydroxy-naphthalen-2-yl)-phenylsulphonamide and 0.48 ml of pyridine in 25 ml methylene chloride while cooling with an ice bath, and the reaction mixture is slowly heated to ambient temperature. Then a further 0.20 ml of pyridine io and 0.10 ml trifluoromethanesulphonic acid anhydride are added while cooling with an ice bath. For working up the reaction mixture is diluted with methylene chloride, washed with dilute sodium carbonate solution, dilute hydrochloric acid and water, dried on magnesium sulphate and evaporated down. The flask residue is stirred with petroleum ether, the precipitate formed is suction filtered and dried.
Yield: 808 mg (78 % of theory) Rf value: 0.85 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 498, 500, 502 [M-H]-The following compounds are obtained analogously to Example XVIII:
(1) 3,5-dichloro-N-(5-trifluoromethanesulphonyloxy-naphthalen-1-yl)-phenylsulphonamide F
O F
0-S,. F
HN, 1, ci /I
CI
Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 517, 519, 521 [M+NH4]+
Example XIX
7-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylic acid HN-'~ O
O=s=0 OH
CI CI
A mixture of 300 mg methyl 7-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carboxylate, 10 ml of 2N sodium hydroxide solution and 10 io ml of methanol is stirred for 6 h at ambient temperature, then the solvent is distilled off in vacuo. The flask residue is acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are dried on magnesium sulphate and evaporated down. The crude product is extracted with diisopropylether, suction filtered and dried.
Yield: 277 mg (96% of theory) Mass spectrum (ESI-): m/z = 394, 396, 398 [M-H]-The following compounds are obtained analogously to Example XIX:
(1) 4-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoic acid H / I OH
O N
I
HN, 1, CI
O
CI
Rf value: 0.56 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(2) 4-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carbonyl]-amino}-methyl)-benzoic acid H / I OH
O N
HN
O=s=O
ciJ CI
Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(3) 3-({[5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl]-amino}-methyl)-benzoic acid /
OH
HN,S~ CI
O
CI
io Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
Example XX
6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid amide O NHZ
HN
O=s=0 CI I CI
2.90 g carbonyldiimidazole are added to 7.20 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid in 70 ml N,N-dimethylformamide and the reaction mixture is heated in a water bath. After cooling to ambient temperature the reaction mixture is stirred for another 5 h, combined with 20 ml concentrated ammonia and stirred overnight. Then the mixture is diluted with ethyl acetate, the organic phase is separated off and the aqueous phase is acidified with concentrated hydrochloric acid. A
precipitate settles out, which is suction filtered and dried.
Yield: 4.50 g (63 % of theory) io Mass spectrum (ESI+): m/z = 395, 397, 399 [M+H]+
The following compounds are obtained analogously to Example XX:
(1) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid amide HN, 1 , cl S-q cl Rf value: 0.20 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 395, 397, 399 [M+H]+
(2) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-(pyridin-4-ylmethyl)-amide N
O N
HN,0 cl cl (The reaction takes place with 4-picolylamine in tetrahydrofuran.) Rf value: 0.25 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 484, 486, 488 [M-H]-(3) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-cyclohexylmethyl-amide H
O N
HN,0 cl cl (The reaction takes place with aminomethylcyclohexane in tetrahydrofuran.) Rf value: 0.80 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 489, 491, 493 [M-H]-(4) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-(pyridin-2-ylmethyl)-amide H
O N
n-N
HN,0 cl cl (The reaction takes place with 2-picolylamine in tetrahydrofuran.) Rf value: 0.52 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 486, 488, 490 [M+H]+
(5) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-(pyridin-3-ylmethyl)-amide H
O N N
~
HN CI
CI
(The reaction takes place with 3-picolylamine in tetrahydrofuran.) Rf value: 0.30 (silica gel, ethyl acetate) Mass spectrum (ESI-): m/z = 484, 486, 488 [M-H]-(6) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-4-cyano-benzylamide N
H
O N
- I
HN, 1, CI
O
CI
(The reaction takes place with 4-cyanobenzylamine in tetrahydrofuran.) 1o Rf value: 0.90 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
(7) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-cyano-benzylamide O N
N
HN, 1, CI
O
CI
(The reaction takes place with 3-cyanobenzylamine in tetrahydrofuran.) Rf value: 0.90 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
(8) 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-3-cyano-benzylamide H
O
i i NI
HN,0 CI
CI
(The reaction takes place with 2-cyanobenzylamine in tetrahydrofuran.) Rf value: 0.37 (silica gel, cyclohexane/ethyl acetate = 1:1) Example XXI
(3,5-dichloro-N-[5-(3-methyl-[1,2,41oxadiazol-5-yl)-naphthalen-2-yll-phenylsulphonamide N
O ,N
HN
O=s=0 CI I CI
185 mg N-hydroxy-acetamidine are added to 1.00 g 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl chloride in 2 ml 2,4,6-trimethylpyridine. The reaction mixture is heated to 110 C and stirred for 6 h at this temperature. After cooling to ambient temperature the mixture is combined with ethyl acetate and water. The organic phase is separated off and washed with 1 N hydrochloric acid, water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue stirred is with methylene chloride, suction filtered and dried.
Yield: 690 mg (66 % of theory) Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI-): m/z = 432, 434, 436 [M-H]-The following compounds are obtained analogously to Example XXI:
(1) (3,5-dichloro-N-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-phenylsulphonamide O-N
. N
HN
O=s=0 CI I CI
Mass spectrum (ESI+): m/z = 434, 436, 438 [M+H]+
(2) (3,5-dichloro-N-[6-(3-phenyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-phenylsulphonamide O-N
HN
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 496, 498, 500 [M+H]+
(3) ethyl 5-[6-(3,5-dichloro-phenylsulphonylamino)-naphthalen-1-yl]-[1,2,4]oxad iazol e-3-carboxyl ate O
o N
O ~N
O=s=0 CI d CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(4) N-[5-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide N-O "1 N
HN
O=s=O
CI Cl Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
(5) 3,5-dichloro-N-[5-(3-phenoxymethyl -[1, 2,4]oxadiazol-5-yl)-naphthalen-2-yl]-phenylsulphonamide O
N
O iN
Nz~
HN
O=s=O
CI CI
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI+): m/z = 526, 528, 530 [M+H]+
(6) N-[5-(3-phenylsuIphonylm ethyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide O
N~S
0 iN
HN
O=s=0 CI CI
Rf value: 0.70 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 572, 574, 576 [M-H]-(7) ethyl 5-[6-(3,5-dichloro-phenylsulphonylamino)-naphthalen-2-yl]-io [1,2,4]oxadiazole-3-carboxylate o-N 0 J\ N 0--\
HN
O=s=0 CI CI
Rf value: 0.61 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(8) N-[6-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide O-N
HN
O=s=0 CI CI
Rf value: 0.63 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 510, 512, 514 [M+H]+
(9) 3,5-dichloro-N-[6-(3-phenoxymethyl -[1, 2,4]oxadiazol-5-yl)-naphthalen-2-yl]-phenylsulphonamide O-N
J:\ N 0-0 HN
O=s=0 CI & CI
Rf value: 0.78 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 526, 528, 530 [M+H]+
(10) N-[6-(3-phenylsuIphonylm ethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide O-N
N~.0 S' o' HN
O=s=0 CI CI
Rf value: 0.51 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI-): m/z = 572, 574, 576 [M-H]-Example XXII
6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carbonyl chloride O cl HN
O=S=0 CI Cl Prepared by reacting 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid with thionyl chloride at reflux temperature.
The following compounds are obtained analogously to Example XXII:
(1) 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carbonyl chloride n cI
HN
O=s=0 CI I d CI
Example XXIII
3,5-dichloro-N-f6-(5-methyl-f 1.3.41oxadiazol-2-yl)-naphthalen-2-yll-phenylsulphonamide NI _ N0 H N
O=s=0 CI I CI
270 mg N-[6-(N'-acetyl-hydrazinocarbonyl)-naphthalen-2-yl]-3,5-dichloro-phenylsulphonamide are dissolved in 2 ml phosphorus oxychloride and stirred for 3 h at 80 C. Then the mixture is added to ice water, the precipitate formed is suction filtered, washed with water and dried. The crude product is stirred with ethanol, finely suspended in the ultrasound bath, suction filtered, washed with diethyl ether and dried.
Yield: 100 mg (39 % of theory) Rf value: 0.75 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 434, 436, 438 [M+H]+
Example XXIV
N-[6-(N'-acetyl-hydrazinocarbonyl)-naphthalen-2-yll-3,5-dichloro-phenylsulphonamide H
HN'N( O O
HN
O=s=0 \
CI I d CI
A mixture of 500 mg 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-2-carbonyl chloride, 250 mg acetic hydrazide and 3 ml 2,4,6-trimethylpyridine in 3 ml N,N-dimethylformamide is stirred overnight at 80 C. Then the mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid and saturated sodium chloride solution, dried on magnesium sulphate and evaporated 1o down. The residue is purified by chromatography through a silica gel column with methylene chloride/methanol (99:1 to 80:20) as eluant.
Yield: 270 mg (50 % of theory) Rf value: 0.58 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 452, 454, 456 [M+H]+
Example XXV
6-pyrimid in-2-yl-naphthalen-2-ylam ine N~
\ \ \N
Prepared by treating tert. butyl (6-pyrimidin-2-yl-naphthalen-2-yl)-carbamate with trifluoroacetic acid in methylene chloride at ambient temperature.
Rf value: 0.20 (silica gel, petroleum ether/ethyl acetate = 2:1) The following compounds are obtained analogously to Example XXV:
(1) 5-pyrimidin-2-yl-naphthalen-1-ylamine N ~N
Rf value: 0.26 (silica gel, petroleum ether/ethyl acetate = 1:1) Example XXVI
6-tert.-butoxycarbonylamino-naphthalen-2-yl-boric acid OH
O Nz~ LOH
ON
H
8.73 ml n-butyllithium solution (1.6M in hexane) are added dropwise to 1.50 g tert. Butyl (6-bromo-naphthalen-2-yl)-carbamate in 15 ml anhydrous io tetrahydrofuran under an argon atmosphere at -70 C. The suspension is stirred for one hour at -50 C, then 1.61 ml triisopropyl borate, dissolved in ml anhydrous tetrahydrofuran, are added dropwise within 5 minutes. The suspension is slowly heated to ambient temperature, combined with 10 ml 1 N
hydrochloric acid and stirred for 20 minutes at ambient temperature. The aqueous phase is saturated with common salt and the organic phase is separated off. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium hydrogen carbonate solution, dried on magnesium sulphate and evaporated down.
The flask residue is chromatographed through a silica gel column with methylene chloride/methanol (98:2 to 95:5) as eluant.
Yield: 590 mg (44 % of theory) Rf value: 0.42 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 288 [M+H]+
The following compounds are obtained analogously to Example XXVI:
(1) 5-tert.-butoxycarbonylamino-naphthalen-1 -yl-boric acid HO,B,OH
C; 6 OUI NH
Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 288 [M+H]+
(2) 6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-boric acid N-O
>
Pa'- N
HO' B, OH
(carried out with tert.-butyllithium and trimethyl borate) io Example XXVII
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(5-oxo-4,5-dihydro-[1,2,41oxadiazol-3-yl)-naphthalen-2-yll-amino}-acetate / N
0 ' )=O
O
~ H
N /
O=s=O
CI I / CI
A solution of 400 mg bis-(trichloromethyl)-carbonate in 10 ml methylene chloride is added dropwise at -60 C to 570 mg tert. butyl {(3,5-dichloro-phenylsulphonyl)-[6-(N-hydroxycarbamimidoyl)-naphthalen-2-yl]-amino}-acetate and 0.35 ml triethylamine in 20 ml methylene chloride. After half an hour the cooling bath is removed and the reaction mixture is stirred overnight.
Then the reaction mixture is diluted with ethyl acetate, washed successively with saturated ammonium chloride, sodium hydrogen carbonate and sodium chloride solution, dried on magnesium sulphate and evaporated down. The residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (9:1 to 0:10).
Yield: 480 mg (80 % of theory) Rf value: 0.70 (silica gel, petroleum ether/ethyl acetate = 2:8) Mass spectrum (ESI-): m/z = 548, 550, 552 [M-H]-Tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetate washed obtained as a by-product.
/O O N-N
O=s=0 CI I CI
Rf value: 0.85 (silica gel, petroleum ether/ethyl acetate = 2:8) Example XXVIII
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(5-morpholin-4-ylmethyl-[1,2,41oxadiazol-3-yl)-naphthalen-2-yll-amino}-acetate N
I e N N
OO
N \ \
O=s=0 CI I CI
A mixture of 100 mg tert. butyl [[5-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate, 20 pl morpholine and 29 mg potassium carbonate in 1 ml N,N-dimethylformamide is stirred overnight at ambient temperature. For working up the reaction mixture is diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with petroleum ether/ethyl acetate (1:1) as eluant.
Yield: 73 mg (67 % of theory) Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 633, 635, 637 [M+H]+
Example XXIX
3,5-dichloro-N-[6-(5-methyl-[1,2,41oxadiazol-3-yl)-naphthalen-1-yll-phenylsulphonamide N-O
/ N
HN,S' CI
/I
O
CI
io 160 mg copper(II)acetate and 247 pl triethylamine are added to 405 mg 6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalene-1-boric acid, 200 mg of 3,5-dichloro-phenylsulphonamide and 100 mg molecular sieve (4 A) in 15 ml methylene chloride and the reaction mixture is stirred for 24 h at ambient temperature. Then the mixture is diluted with ethyl acetate, washed with 1 N
sodium hydroxide solution, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography.
Yield: 120 mg (31 % of theory) Example XXX
3-Bromo-5-chloro-phenylsulphonyl chloride CI
0=s=0 Br CI
A solution of 400 mg sodium nitrite in 0.6 ml of water is added dropwise to 1.03 g 3-bromo-5-chloro-aniline in 2 ml concentrated hydrochloric acid while the mixture is cooled in a bath of ice/common salt. The reaction mixture is stirred for 15 minutes at 0 C and then while being cooled it is added to a mixture of 4 ml of a saturated solution of sulphur dioxide in glacial acetic acid (approx. 30 %) and 200 mg copper(II)chloride-dihydrate in 0.4 ml of water.
The cooling bath is removed and the reaction mixture is stirred for 15 minutes at ambient temperature, then in the water bath with gentle heating until no further development of gas can be detected. Some ice water is then added while cooling with an ice bath. After 5 minutes the precipitate formed is suction filtered, washed with some ice water and dried in the desiccator. The sulphonyl chloride obtained is reacted further without any further purification.
Yield: 1.13 mg (78 % of theory) Example XXXI
tert.-butyl 4-(2-aminomethyl -benzoyl)-piperazine-1-carboxylate O
ON UO
I
I
O
Prepared by hydrogenation of tert.-butyl 4-(2-cyanobenzoyl)-1-piperazine-carboxylate in ethanol/chloroform in the presence of platinum dioxide at ambient temperature and at a partial hydrogen pressure of 50 psi.
Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 320 [M+H]+
The following compounds are obtained analogously to Example XXXI:
(1) (2-aminomethyl-phenyl)-morpholin-4-yl-methanone O N
~~~
O
Mass spectrum (ESI+): m/z = 221 [M+H]+
Example XXXII
Benzyl 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylate o o I
HN,' cl cl 1.12 ml ethyldiisopropylamine and 610 mg 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide-hydrochloride are added to 1.05 g 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid and 0.33 ml benzylalcohol in 20 ml acetonitrile and the reaction mixture is stirred for 1.5 h at ambient temperature. Then another 200 mg 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide-hydrochloride are added and the reaction io mixture is stirred overnight at ambient temperature. Then the reaction mixture is evaporated down and the residue is distributed between tert-butylmethylether and dilute citric acid. The organic phase is washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is stirred with a little methanol, suction filtered, washed with a little methanol and dried.
Yield: 389 mg (30 % of theory) Rf value: 0.80 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 484, 486, 488 [M-H]-Example XXXIII
N-(4-aminomethyl-pyridin-2-yl)-N',N'-dimethyl-ethane-l ,2-diamine N N
H
Prepared by treating 2-(2-dimethylamino-ethylamino)-isonicotinonitrile with hydrogen (50 psi) in the presence of Raney nickel in a mixture of methanol and methanolic ammonia solution at ambient temperature.
Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 195 [M+H]+
The following compounds are obtained analogously to Example XXXIII:
(1) N-(4-aminomethyl-pyridin-2-yl)-N,N',N'-trimethyl-ethane-l,2-diamine N NiN~
I
1o Rf value: 0.10 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 209 [M+H]+
(2) N-(5-aminomethyl-pyridin-2-yl)-N,N',N'-trimethyl-ethane-l,2-diamine NHZ
'NI NN
Rf value: 0.15 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 209 [M+H]+
Example XXXIV
2-(2-dimethylamino-ethylamino)-isonicotinonitrile N
II
N NN
H
Prepared by reacting 2-chloro-4-cyano-pyridine with N,N-dimethyl-ethylenediamine in N,N-dimethylformamide in the presence of potassium carbonate at 100 C.
Rf value: 0.30 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 95:5:1) Mass spectrum (ESI+): m/z = 191 [M+H]+
The following compounds are obtained analogously to Example XXXIV:
(1) 2-[(2-dimethylamino-ethyl)-methyl-amino]-isonicotinonitrile N
N N
(The reaction is carried out in dimethylsulphoxide.) Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. Aqueous io ammonia = 95:5:0.1) Mass spectrum (ESI+): m/z = 205 [M+H]+
(2) 6-[(2-dimethylamino-ethyl)-methyl-amino]-nicotinonitrile N
N NN
(The reaction is carried out in dimethylsulphoxide.) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 95:5:0.1) Mass spectrum (ESI+): m/z = 205 [M+H]+
Example XXXV
Tert. Butyl {(3,5-dichloro-phenylsuIphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,21dioxaborolan-2-yl)-naphthalen-2-yll-amino}-acetate o O To B,O
~N
O=s=0 CI \ I CI
A mixture of 396 mg tert. butyl [(3,5-dichloro-phenylsulphonyl)-(6-trifluoro-methanesulphonyloxy-naphthalen-2-yl)-amino]- }-acetate, 269 pl triethylamine and 26 mg [1,1'-bis-(diphenylphosphino)ferrocene]-dichloro-palladium(II) in 4 ml dioxane under an argon atmosphere is combined with the 327 mg of bis-(pinacolato)-diborane and gently refluxed for 5.5 h. After standing overnight at ambient temperature the reaction mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is purified by 1o chromatography through a silica gel column with petroleum ether/ethyl acetate (95:5 to 90:10) as eluant.
Yield: 216 mg (57 % of theory) Rf value: 0.35 (silica gel, methylene chloride) Mass spectrum (ESI+): m/z = 609, 611, 613 [M+NH4]+
The following compounds are obtained analogously to Example XXXV:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-amino}-acetate O,B.O
O~N` '~ ci O ,S / I
CI
Rf value: 0.77 (silica gel, methylene chloride) Mass spectrum (ESI+): m/z = 609, 611, 613 [M+NH4]+
Example XXXVI
N-(2-chloro-pyrimidin-4-yl)-N,N',N'-timethyl-ethane-l ,2-diamine N
H
CI\/N N
Prepared by reacting 2,4-dichloropyrimidine with N,N,N'-trimethyl -ethane-l,2-diamine in the presence of diisopropylethylamine in tetrahydrofuran at ambient temperature.
Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 215 [M+H]+
The following compounds are obtained analogously to Example XXXVI:
(1) N'-(2-chloro-pyrimidin-4-yl)-N,N-dimethyl-ethane-1,2-diamine N
CI\ N NH
N
(The reaction takes place in N,N-dimethylformamide in the presence of potassium carbonate.) Mass spectrum (ESI+): m/z = 201 [M+H]+
(2) 4-(6-iodo-pyridazin-3-yl)-morpholine ~o N N
(The reaction takes place with 3,6-diiodopyridazine in dioxane in the presence of potassium carbonate.) Mass spectrum (ESI+): m/z = 292 [M+H]+
(3) N'-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-ethane-1,2-diamine H
NN
N
CI
(The reaction takes place in dimethylsulphoxide in the presence of potassium carbonate.) Example XXXVII
tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-4-yl)-naphthalen-1-yll-amino}-acetate o N
O 61 "
CI
io A mixture of 40 mg tert. butyl [[5-(2-chloro-pyrimidin-4-yl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate, 15 pl morpholine and 20 pl diisopropylethylamine in 1 ml isopropanol is heated to 120 C in a microwaveable vessel for 10 minutes. The reaction mixture is evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (85:15) as eluant.
Yield: 28 mg (64 % of theory) Rf value: 0.12 (silica gel, petroleum ether/ethyl acetate = 5:1) The following Examples are obtained analogously to Example XXXVII:
(1) tert. Butyl {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-naphthalen-1-yl]-amino}-acetate CO
N
N N
I /
ON` ~~ YCI
S
O
CI
Rf value: 0.14 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI+): m/z = 629, 631, 633 [M+H]+
Example XXXVIII
6-ftert-butoxycarbonylmethyl-(3,5-dichloro-phenylsuIphonyl)-aminol-naphthalene-2-boric acid Y OH
OO B,OH
N
O=s=0 CI
CI
1o Prepared by treating tert. butyl {(3,5-dichloro-phenylsulphonyl)-[6-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-naphthaIen-2-yl]-amino}-acetate with sodium metaperiodate and ammonium acetate in acetone.
Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 527, 529, 531 [M+NH4]+
Example XXXIX
N'-(5-bromo-pyrazin-2-vl)-N, N-dimethvl-ethane-1,2-diamine N
N\ /NH
Br N
13.79 g sodium hydride (60% in mineral oil) are added batchwise to 24.00 g 5-bromo-pyrazin-2-ylamine and 19.87 g (2-chloro-ethyl)-dimethyl-amine-hydrochloride in 300 ml N,N-dimethylformamide at 0 C. After ten minutes the reaction mixture is heated to 80 C for 2 h. After cooling to ambient temperature the reaction mixture is divided between semi-saturated sodium chloride solution and ethyl acetate. The aqueous phase is extracted with io ethyl acetate and the combined organic phases are dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with methylene chloride/methanol (9:1 to 6:4) as eluant. The crude product is taken up in 150 ml of ethyl acetate and stirred with 12 g activated charcoal. After one hour the activated charcoal is filtered off, the filtrate is evaporated down, stirred with some petroleum ether and stored in the freezer for one hour. Then the petroleum ether is decanted off and the solid remaining is dried under a high vacuum.
Yield: 11.00 g (33 % of theory) Mass spectrum (ESI+): m/z = 245, 247 [M+H]+
Example XL
N'-(6-bromo-pyridazin-3-vl)-N, N-dimethvl-ethane-1,2-diamine H
N NN
Br Prepared by treating N'-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-ethane-1,2-diamine with 48% hydrobromic acid at 100 C.
Mass spectrum (ESI+): m/z = 245, 247 [M+H]+
Example XLI
4-(5-bromo-pyrazin-2-yl)-morpholine ('~ o /N
N
~N
Br 3.18 g N-bromosuccinimide are added at 0 C to 2.95 g 4-pyrazin-2-yl-morpholine in 200 ml methylene chloride and the reaction mixture is heated to ambient temperature overnight with stirring. Then another 400 mg N-bromosuccinimide are added while cooling with an ice bath and the reaction mixture is stirred for a further 3 h. For working up the reaction mixture is washed with water and the organic phase is combined with magnesium io sulphate and silica gel, stirred vigorously for 30 minutes and filtered.
The filter cake is washed with a little methylene chloride followed by 200 ml of ethyl acetate. The combined filtrates are evaporated down. The flask residue is suction-filtered with tert.-butylmethyl ether, washed with a little tert.-butylmethylether and dried.
Yield: 3.05 g (69 % of theory) Rf value: 0.65 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 244, 246 [M+H]+
Preparation of the End compounds Example 1 [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-2-yll-(3,5-dichloro-phenyl-suIphonyl)-aminol-acetic acid N
O H
HOTO
N
O=s=0 CI CI
0.40 ml 1 N sodium hydroxide solution are added to 100 mg methyl [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenyl-suIphonyl)-amino]-acetate in 3 ml of methanol and the suspension is stirred io overnight at ambient temperature. For working up 0.40 ml 1 N hydrochloric acid are added dropwise and the mixture is diluted with approx. 15 ml of water. The precipitate formed is suction filtered and washed with water. The crude product is chromatographed through a silica gel column with ethyl acetate/methanol (100:0 to 98:2) as eluant. The product fractions are evaporated down and the flask residue is taken up in dilute sodium hydroxide solution. The product is precipitated by the addition of dilute hydrochloric acid, suction filtered, washed with water and dried.
Yield: 35 mg (36 % of theory) Rf value: 0.35 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
The following compounds are obtained analogously to Example 1:
(1) [(5-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid N
O Z", HO O
N
O=s=0 CI CI
Rf value: 0.58 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(2) [[5-(4-aminomethyl-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid NHZ
H O N
HO O
N
O=s=O
CI CI
Mass spectrum (ESI+): m/z = 572, 574, 576 [M+H]+
(3) [(3,5-dichloro-phenylsulphonyl)-(6-phenylaminocarbonyl-naphthalen-2-yl)-amino]-acetic acid o ~
HO O N I
~N H
0=s=0 Cl CI
Rf value: 0.25 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(4) [(3,5-dichloro-phenylsulphonyl)-(6-m ethyl aminocarbonyl-naphthalen-2-yl)-amino]-acetic acid O
HO CO H O O X A N
N I A ~ H
O=s=0 CI I CI
Rf value: 0.28 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 467, 469, 471 [M+H]+
(5) [(3,5-dichloro-phenylsulphonyl)-(4-methoxy-naphthalen-2-yl)-amino]-acetic acid HO O '-(' N I
O=s=O
CI I CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 440, 442, 444 [M+H]+
(6) [(5-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H
O N O
I
O
HO CI
, O
CI
Rf value: 0.58 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(7) [(3,5-dichloro-phenylsulphonyl)-(5-m ethyl aminocarbonyl-naphtha len-1-yl)-amino]-acetic acid H
O N", O
HO CI
O
CI
Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 467, 469, 471 [M+H]+
(8) 4-[({5-[carboxymethyl-(3,5-dichloro-phenylsulphonyl)-amino]-naphthalen-1-ylcarbonyl}-amino)-methyl]-benzoic acid H / I OH
O N
O
HO~N O ci O S /
CI
Rf value: 0.30 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 587, 589, 591 [M+H]+
Example 2 [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yll-(3,5-dichloro-phenylsulphonyl)-aminol-acetic acid NHZ
H O N
HO O
N
O=s=O
ciJ CI
A mixture of 200 mg methyl [[5-(4-carbamimidoyl-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetate hydrochloride, 500 mg sodium carbonate, 2.5 ml of water and 5 ml of methanol is stirred overnight at ambient temperature and then refluxed for 8 h. After cooling to ambient temperature 1 ml of 1 N sodium hydroxide solution is added. The reaction mixture is stirred overnight at ambient temperature, diluted with some water and acidified with 2N hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried. The crude product thus obtained is stirred with methanol, suction filtered, washed 1o with methanol and ether and dried.
Yield: 90 mg (49 % of theory) Rf value: 0.30 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
Example 3 [(3,5-dichloro-phenylsuIphonyl)-(5-m ethyl am inocarbonyl-naphthalen-2-yl)-aminol-acetic acid H
O N
HO O
N I
O=s=0 CI I CI
10 ml trifluoroacetic acid are added to 3.66 g tert. butyl [(3,5-dichloro-phenylsulphonyl)-(5-methyl aminocarbonyl-naphthalen-2-yl)-amino]-acetate in 50 ml methylene chloride and the reaction mixture is stirred for 4.5 h at ambient temperature. Then the reaction mixture is evaporated down using the rotary evaporator and the flask residue is dissolved with dilute sodium hydroxide solution. This aqueous solution is washed with a little methylene chloride and acidified with 1 N hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried in the desiccator.
Yield: 3.04 g (Yield: 93% of theory) Rf value: 0.30 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI-): m/z = 465, 467, 469 [M-H]-The following compounds are obtained analogously to Example 3:
(1) [[5-(cyclohexylmethyl-aminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O NiD
HO O
N
O=s=0 CI I CI
Rf value: 0.75 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 549, 551, 553 [M+H]+
(2) [(3,5-dichloro-phenylsulphonyl)-(5-phenylaminocarbonyl-naphthalen-2-yl)-amino]-acetic acid H
O N ~
HO O I
N
O=s=0 CI I CI
Rf value: 0.63 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(3) {(3,5-dichloro-phenylsulphonyl)-[5-(3,4-dihydro-1 H-isoquinoline-2-carbonyl)-naphthalen-2-yl]-amino}-acetic acid O
HO O
N
O=s=0 CI CI
Rf value: 0.82 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 569, 571, 573 [M+H]+
(4) [(3,5-dichloro-phenylsulphonyl)-(5-phenylethylaminocarbonyl-naphthalen-2-yl)-amino]-acetic acid H
O N
HO O N
N
O=s=0 CI CI
Rf value: 0.75 (silica gel, methylene chloride/methanol/conc. Aqueous 1o ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(5) [[5-(N-benzyl-N-methyl-aminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid I
O N () HO O
N
O=s=0 Cl CI
Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. Aqueous ammonia = 16:4:1) Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(6) [(6-aminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O
N
O=s=0 CI CI
Rf value: 0.34 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI+): m/z = 453, 455, 457 [M+H]+
io (7) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl -[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid HO, O AN /
N
O=s=O
CI CI
Rf value: 0.10 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(8) [(3,5-dichloro-phenylsulphonyl)-(6-oxazol-2-yl-naphthalen-2-yl)-amino]-acetic acid HO O N
N
O=s=O
CI CI
Rf value: 0.10 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 475, 477, 479 [M-H]-(9) [(3,5-dichloro-phenylsulphonyl)-naphthalen-1-yl-amino]-acetic acid c YCI
CI
Rf value: 0.20 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 408, 410, 412 [M-H]-io (10) [(6-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O
HO O : /e N~
N I H
0=s=0 CI I & CI
Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(11) {(3,5-dichloro-phenylsulphonyl))-[5-(pyrrolidine-1-carbonyl)-naphthalen-2-yl]-amino}-acetic acid O N'D
HoTO
N
0=s=0 CI CI
Mass spectrum (ESI+): m/z = 507, 509, 511 [M+H]+
(12) [(3,5-dichloro-phenylsulphonyl)-(5-isopropylaminocarbonyl-naphthalen-2-yl)-amino]-acetic acid H
O N`r HOTO
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 495, 497, 499 [M+H]+
(13) [(5-aminocarbonyl-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid HO O
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 470, 472, 474[M+NH4]+
io (14) {(3,5-dichloro-phenylsulphonyl)-[5-(2-hydroxy-ethylaminocarbonyl)-naphthalen-2-yl]-amino}-acetic acid H
Ho TO
N
O=s=0 CI CI
Mass spectrum (ESI+): m/z = 497, 499, 501 [M+H]+
(15) [(5-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dimethyl-phenylsulphonyl)-amino]-acetic acid O N I
HOTO
N I
O=s=0 Jta"
Rf value: 0.15 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 503 [M+H]+
(16) [(6-benzylaminocarbonyl-naphthalen-2-yl)-(3,5-dimethyl-phenylsulphonyl)-amino]-acetic acid O
HO O N
N H
O=s=0 Rf value: 0.28 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI+): m/z = 503 [M+H]+
(17) [(7-benzoylamino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H N N
O=s=0 H
CI I CI
Mass spectrum (ESI-): m/z = 527, 529, 531 [M-H]-(18) [{7-[(4-chloro-pyridin-2-carbonyl)-amino]-naphthalen-2-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid HO f I / /
N CI
H I
O=S=O N
CI CI
Mass spectrum (ESI-): m/z = 562, 564, 566, 568 [M-H]-(19) [[7-(3-benzyl-ureido)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid HOf I 0 N 14- 1-:11 NAN
O=S=O H H
CI CI
Mass spectrum (ESI-): m/z = 556, 558, 560 [M-H]-(20) [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-3-yl-naphthalen-2-yl)-amino]-io acetic acid N
T I
N
O=S=0 Cl CI
Rf value: 0.55 (silica gel, ethyl acetate/acetic acid = 99:1) Mass spectrum (ESI+): m/z = 487, 489, 491 [M+H]+
(21) {(3,5-dichloro-phenylsulphonyl)-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid HO
N
O=S=0 Nom( CI CI
Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(22) {(3,5-dichloro-phenylsuIphonyl)-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid o-'~
N N N
HO O
N
O=s=0 CI CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(23) {(3,5-dichloro-phenylsuIphonyl)-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid N--~
0 ,N
HO O C~
N
O=s=0 CI CI
Rf value: 0.30 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(24) {(3,5-dichloro-phenylsuIphonyl)-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O-N~
Ho TO N
N
O=s=0 CI Cl Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(25) {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O-N
HO O ~N
N
O=s=0 CI I CI
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 554, 556, 558 [M+H]+
(26) {(3,5-dichloro-phenylsulphonyl)-[5-(5-phenyl-[1,2,4]oxadiazol-3-yl)-io naphthalen-2-yl]-amino}-acetic acid oP
N N N
HOTO
N
O=s=O
CI I CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 554, 556, 558 [M+H]+
(27) {(3,5-dichloro-phenylsulphonyl)-[5-(5-benzyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid N N N
HOTO
N I
O=s=0 CI CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(28) {(3,5-dichloro-phenylsulphonyl)-[5-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid N N N
HOTO
N I
O=s=0 CI Cl Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 520, 522, 524 [M+H]+
(29) {(3,5-dichloro-phenylsulphonyl)-[6-(5-phenyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid N-O _ HO O jCOA N /
N
0=s=0 CI CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 554, 556, 558 [M+H]+
(30) {(3,5-dichloro-phenylsulphonyl)-[6-(5-phenyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid HO O
N
N
O=s=O
CI CI
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(31) {(3,5-dichloro-phenylsulphonyl)-[6-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid H O O I
CON
N
O=s=0 CI CI
1o Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 520, 522, 524 [M+H]+
(32) {(3,5-dichloro-phenylsulphonyl)-[5-(5-hydroxy-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid OH
O
NN N
HO O
N
O=s=0 CI CI
Rf value: 0.30 (silica gel, methylene chloride/methanol/acetic acid = 5:1:0.1) Mass spectrum (ESI+): m/z = 494, 496, 498 [M+H]+
(33) {(3,5-dichloro-phenylsulphonyl)-[5-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid cI
cI
o cI
N
HOTO
N
O=s=0 CI CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESI+): m/z = 594, 596, 598, 600 [M+H]+
(34) {(3,5-dichloro-phenylsulphonyl)-[5-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O
N o 0 ,N
Ho o N
O=s=0 CI d CI
Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) io Mass spectrum (ESI+): m/z = 550, 552, 554 [M+H]+
(35) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1.3.4]oxadiazol-2-yl)-naphthalen-2-yl]-amino}-acetic acid N-N
HO ~
,O IDCJ--,- 0 N
O=s=0 CI CI
Rf value: 0.26 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(36) {(3,5-dichloro-phenylsulphonyl)-[5-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid N-O ,N
HOTO
N I ~
O=s=O
CI I & CI
Rf value: 0.60 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(37) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyloxymethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid N--( -0 O N
HO O N~
N
O=s=O
CI I CI
Rf value: 0.70 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESI-): m/z = 582, 584, 586 [M-H]-(38) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenylsulphonylmethyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid N
0 iN
HO 0 i N
O=s=0 CI I CI
Rf value: 0.50 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESI-): m/z = 630, 632, 634 [M-H]-(39) [(5-benzoylamino-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid HN
I C;) 0 ~N`S 0 HO CI
6' f CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 527, 529, 531 [M-H]-(40) [(3,5-dichloro-phenylsulphonyl)-(5-phenylacetylamino-naphthalen-1-yl)-amino]-acetic acid HN
HO CI
S I
O
Cl Rf value: 0.32 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 541, 543, 545 [M-H]-(41) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-prop ionylamino)-naphthalen-1-yl]-amino}-acetic acid O
HN
I C;) 0 O
)LI-IN` O CI
HO S
O
CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 555, 557, 559 [M-H]-(42) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-ureido)-naphthalen-1-yl]-amino}-acetic acid HN NJO
H
I
O
HO CI
O
CI
Rf value: 0.28 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 542, 544, 546 [M-H]-(43) [[5-(3-benzyl-ureido)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O
HNN II \~
O
HO CI
O
CI
Rf value: 0.26 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 556, 558, 560 [M-H]-(44) [{5-[(4-chloro-pyridin-2-yl-carbonyl)-amino]-naphthalen-1-yl}-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid N
HN
CI
HO CI
O
CI
Rf value: 0.45 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 564, 566, 568 [M+H]+
(45) [(3,5-dichloro-phenylsulphonyl)-(5-phenylaminocarbonyl-naphthalen-1-yl)-amino]-acetic acid H
O cC
N` O
HO S CI
O I
CI
Rf value: 0.17 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 529, 531, 533 [M+H]+
(46) [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-4-yl-naphthalen-2-yl)-amino]-acetic acid N
HO O I I
N
O=s=O
CI I CI
Rf value: 0.60 (silica gel, ethyl acetate/acetic acid = 99:1) Mass spectrum (ESI+): m/z = 487, 489, 491 [M+H]+
(47) [(3,5-dichloro-phenylsulphonyl)-(6-furan-3-yl-naphthalen-2-yl)-amino]-acetic acid HO O O Nz~ N
o=s=o CI CI
Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate/acetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 474, 476, 478 [M-H]-(48) {(3,5-dichloro-phenylsulphonyl)-[6-(3,5-dimethyl-isoxazol-4-yl)-naphthalen-2-yl]-amino}-acetic acid ,N
HO O I O
N / /
o=s=o CI CI
Rf value: 0.57 (silica gel, cyclohexane/ethyl acetate/acetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 503, 505, 507 [M-H]-(49) {(3,5-dichloro-phenylsulphonyl)-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetic acid O_~
N N
O
HON 0 O / Ycl CI
Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(50) [(3,5-dichloro-phenylsulphonyl)-(6-furan-2-yl-naphthalen-2-yl)-amino]-acetic acid HO 0 I 0 Nz~ N
O=s=0 CI CI
Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate/acetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 474, 476, 478 [M-H]-(51) [(5-aminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid I
O
N- , HO ICI
CI
Rf value: 0.52 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 453, 455, 457 [M+H]+
(52) [(3,5-dichloro-phenylsulphonyl)-(6-pyrimidin-2-yl-naphthalen-2-yl)-amino]-acetic acid HO O
N
N
O=s=0 CI I CI
Rf value: 0.32 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 488, 490, 492 [M+H]+
N
N
O=s=0 CI I CI
Rf value: 0.32 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 488, 490, 492 [M+H]+
(53) [(3,5-dichloro-phenylsulphonyl)-(5-pyrimidin-2-yl-naphthalen-1-yl)-amino]-acetic acid N ~N
O
Ycl HO'N O
CI
Rf value: 0.30 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 488, 490, 492 [M+H]+
O
Ycl HO'N O
CI
Rf value: 0.30 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 488, 490, 492 [M+H]+
(54) [(3,5-dichloro-phenylsulphonyl)-(6-pyridin-2-yl-naphthalen-2-yl)-amino]-io acetic acid ~I
HO O ~N
N
O=s=0 CI I CI
Rf value: 0.65 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 487, 489, 491 [M+H]+
HO O ~N
N
O=s=0 CI I CI
Rf value: 0.65 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 487, 489, 491 [M+H]+
(55) [(3,5-dichloro-phenylsulphonyl)-(5-phenylethyl-aminocarbonyl-naphthalen-1-yl)-amino]-acetic acid H
O N
HON ,SO / CI
I
Cl Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
O N
HON ,SO / CI
I
Cl Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H]+
(56) [(3,5-dichloro-phenylsulphonyl)-(6-methoxy-naphthalen-1-yl)-amino]-acetic acid 0~
CI
Rf value: 0.13 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 438, 440, 442 [M-H]-(57) {(3,5-dichloro-phenylsulphonyl)-[6-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O-N O
HO TO N
O
N
O=s=0 Rf value: 0.33 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 550, 552, 564 [M+H]+
CI
Rf value: 0.13 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI-): m/z = 438, 440, 442 [M-H]-(57) {(3,5-dichloro-phenylsulphonyl)-[6-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O-N O
HO TO N
O
N
O=s=0 Rf value: 0.33 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 550, 552, 564 [M+H]+
(58) {[6-(3-benzyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino}-acetic acid O-N
N -O=s=0 Rf value: 0.34 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
N -O=s=0 Rf value: 0.34 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(59) {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenyloxymethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid o-N
HO
TO N O /
N
O=S=0 CI CI
Rf value: 0.32 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 582, 584, 586 [M-H]-(60) {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenylsulphonylmethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O-N
HO 0 N~ .0 111 S~
N 0' b o=s=o CI CI
1o Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 630, 632, 634 [M-H]-(61) {(3,5-dichloro-phenylsulphonyl)-[6-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid HO H
CO
N
O=s=O
ciJ CI
Rf value: 0.12 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 492, 494, 496 [M-H]-(62) {(3,5-dichloro-phenylsulphonyl)-[6-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid ~O
HO O N' N
N
O=s=0 ciJ CI
Rf value: 0.43 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 506, 508, 510 [M-H]-(63) {(3,5-dichloro-phenylsulphonyl)-[5-(5-morpholin-4-ylmethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid N
0_\\ N N
HOO
O=s=0 ciJ Cl Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 577, 579, 581 [M+H]+
HO
TO N O /
N
O=S=0 CI CI
Rf value: 0.32 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 582, 584, 586 [M-H]-(60) {(3,5-dichloro-phenylsulphonyl)-[6-(3-phenylsulphonylmethyl -[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid O-N
HO 0 N~ .0 111 S~
N 0' b o=s=o CI CI
1o Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 630, 632, 634 [M-H]-(61) {(3,5-dichloro-phenylsulphonyl)-[6-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid HO H
CO
N
O=s=O
ciJ CI
Rf value: 0.12 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 492, 494, 496 [M-H]-(62) {(3,5-dichloro-phenylsulphonyl)-[6-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid ~O
HO O N' N
N
O=s=0 ciJ CI
Rf value: 0.43 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 506, 508, 510 [M-H]-(63) {(3,5-dichloro-phenylsulphonyl)-[5-(5-morpholin-4-ylmethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid N
0_\\ N N
HOO
O=s=0 ciJ Cl Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 577, 579, 581 [M+H]+
(64) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetic acid N-O
i N
O
HON S / CI
O
CI
Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(65) ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-4-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid N H O N
HON. O ci ,S
O
ci Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
i N
O
HON S / CI
O
CI
Mass spectrum (ESI-): m/z = 490, 492, 494 [M-H]-(65) ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-4-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid N H O N
HON. O ci ,S
O
ci Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(66) [[5-(cyclohexylmethyl-aminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H
O N
HO1O ci S
ci Rf value: 0.43 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 549, 551, 553 [M+H]+
O N
HO1O ci S
ci Rf value: 0.43 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 549, 551, 553 [M+H]+
(67) ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-2-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid H
O N
ON
HO1O ci S
ci Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
O N
ON
HO1O ci S
ci Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(68) ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid H
O N N
HON. 1O ci S/ I
ci Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
O N N
HON. 1O ci S/ I
ci Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(69) [(3,5-dibromo-phenylsulphonyl)-(naphthalen-1-yl)-amino]-acetic acid c O
HON SO / Br o I
Br 1o Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 2:3) Mass spectrum (ESI+): m/z = 498, 500, 502 [M+H]+
HON SO / Br o I
Br 1o Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 2:3) Mass spectrum (ESI+): m/z = 498, 500, 502 [M+H]+
(70) [(3-bromo-5-methyl-phenylsulphonyl)-(naphthalen-1-yl)-amino]-acetic acid O
O
N S /
HO o I
Br Rf value: 0.56 (silica gel, petroleum ether/ethyl acetate = 2:3) Mass spectrum (ESI+): m/z = 434, 536 [M+H]+
O
N S /
HO o I
Br Rf value: 0.56 (silica gel, petroleum ether/ethyl acetate = 2:3) Mass spectrum (ESI+): m/z = 434, 536 [M+H]+
(71) [(3-bromo-5-chloro-phenylsulphonyl)-(naphthalen-1-yl)-amino]-acetic acid c O
~ g, / CI
HON~
O
Br Rf value: 0.66 (silica gel, petroleum ether/ethyl acetate = 2:3) Mass spectrum (ESI-): m/z = 452, 554, 556 [M-H]-(72) [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid N
H
O N
I
O
S / CI
HO'N O
o I
CI
Rf value: 0.30 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
~ g, / CI
HON~
O
Br Rf value: 0.66 (silica gel, petroleum ether/ethyl acetate = 2:3) Mass spectrum (ESI-): m/z = 452, 554, 556 [M-H]-(72) [[5-(4-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid N
H
O N
I
O
S / CI
HO'N O
o I
CI
Rf value: 0.30 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(73) [[5-(3-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O N
N
O
HO~N O CI
O S
CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 566, 568, 570 [M-H]-(74) [[5-(2-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H
O N
HON' O CI
CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
N
O
HO~N O CI
O S
CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 566, 568, 570 [M-H]-(74) [[5-(2-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H
O N
HON' O CI
CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 568, 570, 572 [M+H]+
(75) {(3,5-dichloro-phenylsulphonyl)-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-1-yl]-amino}-acetic acid N
I
O
O-N ~N,s CI
O
CI
Rf value: 0.62 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) io Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
I
O
O-N ~N,s CI
O
CI
Rf value: 0.62 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) io Mass spectrum (ESI+): m/z = 492, 494, 496 [M+H]+
(76) {(3,5-dichloro-phenylsulphonyl)-[5-(2-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetic acid H
O N
O~
I
HON. 1O CI
S/ I
CI
Rf value: 0.32 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
O N
O~
I
HON. 1O CI
S/ I
CI
Rf value: 0.32 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(77) {(3,5-dichloro-phenylsulphonyl)-[5-(3-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetic acid HON, 1O CI
S/
CI
Rf value: 0.31 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
S/
CI
Rf value: 0.31 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(78) {(3,5-dichloro-phenylsulphonyl)-[5-(4-methoxy-benzylcarbonylamino)-naphthalen-1-yl]-amino}-acetic acid H
O N
I
o CI
1o Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
O N
I
o CI
1o Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(79) [[3-(phenylsulphonyl-methyl-amino)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid I/
0=s=0 HO'N , / CI
o CI
Mass spectrum (ESI-): m/z = 577, 579, 581 [M-H]-(80) [(4-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H
O N
N- , 0 HO Ycl CI
Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
0=s=0 HO'N , / CI
o CI
Mass spectrum (ESI-): m/z = 577, 579, 581 [M-H]-(80) [(4-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H
O N
N- , 0 HO Ycl CI
Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(81) [[5-(3-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid O N O
NHZ
HO O CI
N
CI
Rf value: 0.19 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
NHZ
HO O CI
N
CI
Rf value: 0.19 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
(82) ((3,5-dichloro-phensulphonyl)-{5-[(pyridin-4-ylmethyl)-aminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid / N
O N
HOMO
N
o=s=o ciJ CI
Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(82) ((3,5-dichloro-phensulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid H
O N N
HOMO
N
o=s=o ciJ Cl Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(84) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(morpholin-4-ylcarbonyl)-io benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid O
O
HO~NI O CI
O
CI
Rf value: 0.21 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(85) [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H NHZ
O
HO~N O CI
/
O
S CI
Rf value: 0.20 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
(86) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid O
H N
HO t 0 N
O=s=0 ciJ CI
Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(87) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid O ~\
H / I N I
HO t 0 N
O=s=0 ciJ Cl Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(88) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid O N LNH
HO~N O CI
S
O
CI
Rf value: 0.66 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(89) ((3,5-dichloro-phenylsulphonyl)-{5-[3-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid O N O
1 CN) O
O
CI
O
CI
Rf value: 0.24 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(90) ((3,5-dichloro-phenylsulphonyl)-{5-[3-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid CN~
N
HON, 0 CI
O
CI
Rf value: 0.66 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(91) ((3,5-dichloro-phenylsulphonyl)-{5-[2-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid H
O N
~NH
0=s=0 CI
CI
Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(92) ((3,5-dichloro-phenylsulphonyl)-{5-[2-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid H
O N
O
O
HO ,O CI
S/
Cl Rf value: 0.55 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(93) ((3,5-dichloro-phenylsulphonyl)-{5-[2-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid H
O N
O N
~NH
HO CI
O /
CI
Rf value: 0.70 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(94) {(3,5-dichloro-phenylsulphonyl)-[5-(3-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid H
O N N
I
HO~N 0 ci S /
O
CI
Rf value: 0.40 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
(95) {(3,5-dichloro-phenylsulphonyl)-[5-(4-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid N
N
O
O
HO~N O CI
O
CI
Rf value: 0.45 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
(96) {[5-(2-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino}-acetic acid H
O N
O NHZ
O
HON O CI
1, O
CI
Rf value: 0.31 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
(97) {(3,5-dichloro-phenylsulphonyl)-[5-(4-methylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid O
HO"U , O CI
O
CI
Rf value: 0.17 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(98) {(3,5-dichloro-phenylsulphonyl)-[5-(3-methylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid H H
O N N
/ I
CI
HO~N 0 S
O
CI
Rf value: 0.30 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(99) {(3,5-dichloro-phenylsulphonyl)-[5-(4-dimethyl aminocarbonyl-io benzylaminocarbonyl)-naphthalen-2-yl]-amino}-acetic acid O N & N
HO(O
N
O=s=0 ciJ Cl Rf value: 0.16 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
(100) {(3,5-dichloro-phenylsulphonyl)-[5-(3-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yl]-amino}-acetic acid H
O N N~
HO O O
N
O=s=O
CI
CI
Rf value: 0.20 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
(101) [[3-(N-benzyl-N-methyl-aminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid :N
O
O
HON' CI
O
CI
Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 1:1) Rf value: 0.20 (silica gel, methylene chloride/methanol = 95:5) io Mass spectrum (ESI+): m/z = 574, 576, 578 [M+NH4]+
(102) [(3,5-dichloro-phenylsulphonyl)-[3-(N-methyl-N-phenyl-aminocarbonyl)-naphthalen-1-yl]-acetic acid aN
O
HO~N~s' CI
CI
Rf value: 0.13 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(103) [(3,5-dichloro-phenylsulphonyl)-(5-{[6-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl]-aminocarbonyl}-naphthalen-1-yl)-amino]-acetic acid H
N
I
O N N
O
HO N, 0 ci O
ci Rf value: 0.70 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
(104) [(3,5-dichloro-phenylsulphonyl)-(5-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-aminocarbonyl}-naphthalen-1-yl)-amino]-acetic acid N
H
O N I NH
HO'N, '' ci S
O
CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
(105) {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid N
H
O N I N
O
HO~N~ ' CI
O
CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(106) {(3,5-dichloro-phenylsulphonyl)-[5-({6-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-3-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid N
H O N N I
O
HO"U~N, O CI
O
CI
io Rf value: 0.70 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(107) [(3,5-dichloro-phenylsulphonyl)-(5-{[6-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl]-aminocarbonyl}-naphthalen-2-yl)-amino]-acetic acid H
NN
I
I
O H N
HOMO
N
0=s=0 ciJ CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
(108) {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-am inocarbonyl)-naphthalen-2-yl]-amino}-acetic acid N
H I
O N N' 'N~
HO T, N
o=s=o Cl CI
io Rf value: 0.70 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(109) {(3,5-dichloro-phenylsulphonyl)-[5-({6-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-3-ylmethyl}-am inocarbonyl)-naphthalen-2-yl]-amino}-acetic acid / N
O N I
H0_0 N
0=s=0 ciJ CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(110) [(3,5-dichloro-phenylsulphonyl)-(5-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-carbamoyl}-naphthalen-2-yl)-amino]-acetic acid N
H I
O N N' 'N~
H
N
o=s=o Cl CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), 1o acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
(111) {(3,5-dichloro-phenylsulphonyl)-[6-(4-piperazin-1-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetic acid N
o=s=o CI I CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 572, 574, 576 [M+H]+
(112) {(3,5-dichloro-phenylsulphonyl)-[5-(4-piperazin-1-yl-pyrimidin-2-yl)-naphthalen-1-yl]-amino}-acetic acid H
N
N ~N
O
CI
Rf value: 0.73 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 572, 574, 576 [M+H]+
(113) {(3,5-dichloro-phenylsulphonyl)-[6-(2-morpholin-4-yl-pyrimidin-4-yl)-naphthalen-2-yl]-amino}-acetic acid N
HO O / N
N
O=s=O
CI I CI
Rf value: 0.45 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI-): m/z = 571, 573, 575 [M-H]-(114) [(3,5-dichloro-phenylsulphonyl)-(6-{4-[N-(2-dimethylamino-ethyl)-N-methyl-amino]-pyrimidin-2-yl}-naphthalen-2-yl)-amino]-acetic acid HO O N I N_ N
O=s=0 N
ciJ CI
Rf value: 0.68 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 588, 590, 592 [M+H]+
(115) {(3,5-dichloro-phenylsulphonyl)-[5-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-1-yl]-amino}-acetic acid ~o NJ
N ~N
O
HO N 0 O ci CI
Rf value: 0.15 (silica gel, methylene chloride/methanol = 95:5) io Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(116) ((3,5-dichloro-phenylsulphonyl)-{6-[4-(2-dimethylamino-ethylamino)-pyrimid in-2-yl]-naphthalen-2-yl}-amino)-acetic acid H N
O=s=0 N
Cl CI
Rf value: 0.67 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 574, 576, 578 [M+H]+
(117) {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-4-yl)-naphthalen-1-yl]-amino}-acetic acid O
N
O
CI
HON O
CI
Rf value: 0.33 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(118) {(3,5-dichloro-phenylsulphonyl)-[6-(6-morpholin-4-yl-pyridazin-3-yl)-naphthalen-2-yl]-amino}-acetic acid rO
N N NJ
HOMO
N
O=s=0 ciJ CI
Rf value: 0.30 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(119) {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-naphthalen-1-yl]-amino}-acetic acid O
N
N N
I /
O
HON` SO CI
/
O
CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(120) ((3,5-dichloro-phenylsulphonyl)-{6-[5-(2-dimethylamino-ethylamino)-pyrazin-2-yl]-naphthalen-2-yl}-amino)-acetic acid H
NYN
J
HOMO N
N
O=s=0 ciJ CI
Rf value: 0.58 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) io Mass spectrum (ESI+): m/z = 574, 576, 578 [M+H]+
(121) ((3,5-dichloro-phenylsulphonyl)-{6-[6-(2-dimethylamino-ethylamino)-pyridazin-3-yl]-naphthalen-2-yl}-amino)-acetic acid H
N N N
HOMO
N
O=s=0 ciJ Cl Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 574, 576, 578 [M+H]+
(122) {(3,5-dichloro-phenylsulphonyl)-[6-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetic acid N
H00 ~N
N
O=s=0 ciJ CI
Rf value: 0.45 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(123) {(3,5-dichloro-phenylsulphonyl)-[6-(5-morpholin-4-yl-pyrazin-2-yl)-naphthalen-2-yl]-amino}-acetic acid ro /N J
N I
HOMO N
N \ \
O=s=0 ciJ Cl Rf value: 0.36 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(124) [(3,5-dichloro-phenylsulphonyl)-quinolin-8-yl-amino]-acetic acid O
~ g, CI
HON~
I
CI
Rf value: 0.50 (silica gel, methylene chloride/methanol = 15:1) Mass spectrum (ESI+): m/z = 411, 413, 415 [M+H]+
(125) [(3,5-dichloro-phenylsuIphonyl)-(6-methoxy-quinolin-8-yl)-amino]-acetic acid I
O
O N
HO'N , / CI
o I
CI
Rf value: 0.60 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) io Mass spectrum (ESI+): m/z = 441, 443, 445 [M+H]+
Example 4 Coated tablets containing 75 mg of active substance 1 tablet core contains:
active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hyd roxypropyl methylcel I u lose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvin-ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate.
This granulate is compressed in a tablet-making machine to form tablets of the desired shape.
Weight of core: 230 mg die: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.
Weight of coated tablet: 245 mg.
Example 5 Tablets containing 100 mg of active substance Composition:
1 tablet contains:
active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50 C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
Example 6 Tablets containing 150 mg of active substance io Composition:
1 tablet contains:
active substance 50.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45 C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
Weight of tablet: 300 mg die: 10 mm, flat Example 7 Hard gelatine capsules containing 150 mg of active substance 1 capsule contains:
active substance 150.0 mg corn starch (dried approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg Preparation:
The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.
Example 8 Suppositories containing 150 mg of active substance 1 suppository contains:
active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg Preparation:
After the suppository mass has been melted the active substance is homogeneously 3o distributed therein and the melt is poured into chilled moulds.
Example 9 Suspension containing 50 mg of active substance 100 ml of suspension contain:
active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. Water ad 100 ml Preparation:
The distilled water is heated to 70 C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air.
5 ml of suspension contain 50 mg of active substance.
Example 10 Ampoules containing 10 mg active substance Composition:
active substance 10.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
Example 11 Ampoules containing 50 mg of active substance Composition:
active substance 50.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
O N
HOMO
N
o=s=o ciJ CI
Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(82) ((3,5-dichloro-phensulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid H
O N N
HOMO
N
o=s=o ciJ Cl Mass spectrum (ESI+): m/z = 544, 546, 548 [M+H]+
(84) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(morpholin-4-ylcarbonyl)-io benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid O
O
HO~NI O CI
O
CI
Rf value: 0.21 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(85) [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid H NHZ
O
HO~N O CI
/
O
S CI
Rf value: 0.20 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
(86) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid O
H N
HO t 0 N
O=s=0 ciJ CI
Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(87) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid O ~\
H / I N I
HO t 0 N
O=s=0 ciJ Cl Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(88) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid O N LNH
HO~N O CI
S
O
CI
Rf value: 0.66 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(89) ((3,5-dichloro-phenylsulphonyl)-{5-[3-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid O N O
1 CN) O
O
CI
O
CI
Rf value: 0.24 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(90) ((3,5-dichloro-phenylsulphonyl)-{5-[3-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid CN~
N
HON, 0 CI
O
CI
Rf value: 0.66 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(91) ((3,5-dichloro-phenylsulphonyl)-{5-[2-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-2-yl}-amino)-acetic acid H
O N
~NH
0=s=0 CI
CI
Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(92) ((3,5-dichloro-phenylsulphonyl)-{5-[2-(morpholin-4-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid H
O N
O
O
HO ,O CI
S/
Cl Rf value: 0.55 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 656, 658, 660 [M+H]+
(93) ((3,5-dichloro-phenylsulphonyl)-{5-[2-(piperazin-1-ylcarbonyl)-benzylaminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid H
O N
O N
~NH
HO CI
O /
CI
Rf value: 0.70 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 655, 657, 659 [M+H]+
(94) {(3,5-dichloro-phenylsulphonyl)-[5-(3-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid H
O N N
I
HO~N 0 ci S /
O
CI
Rf value: 0.40 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
(95) {(3,5-dichloro-phenylsulphonyl)-[5-(4-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid N
N
O
O
HO~N O CI
O
CI
Rf value: 0.45 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
(96) {[5-(2-aminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino}-acetic acid H
O N
O NHZ
O
HON O CI
1, O
CI
Rf value: 0.31 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 586, 588, 590 [M+H]+
(97) {(3,5-dichloro-phenylsulphonyl)-[5-(4-methylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid O
HO"U , O CI
O
CI
Rf value: 0.17 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(98) {(3,5-dichloro-phenylsulphonyl)-[5-(3-methylaminocarbonyl-benzylaminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid H H
O N N
/ I
CI
HO~N 0 S
O
CI
Rf value: 0.30 (silica gel, toluene/dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI+): m/z = 600, 602, 604 [M+H]+
(99) {(3,5-dichloro-phenylsulphonyl)-[5-(4-dimethyl aminocarbonyl-io benzylaminocarbonyl)-naphthalen-2-yl]-amino}-acetic acid O N & N
HO(O
N
O=s=0 ciJ Cl Rf value: 0.16 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
(100) {(3,5-dichloro-phenylsulphonyl)-[5-(3-dimethylaminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yl]-amino}-acetic acid H
O N N~
HO O O
N
O=s=O
CI
CI
Rf value: 0.20 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 614, 616, 618 [M+H]+
(101) [[3-(N-benzyl-N-methyl-aminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid :N
O
O
HON' CI
O
CI
Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 1:1) Rf value: 0.20 (silica gel, methylene chloride/methanol = 95:5) io Mass spectrum (ESI+): m/z = 574, 576, 578 [M+NH4]+
(102) [(3,5-dichloro-phenylsulphonyl)-[3-(N-methyl-N-phenyl-aminocarbonyl)-naphthalen-1-yl]-acetic acid aN
O
HO~N~s' CI
CI
Rf value: 0.13 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI+): m/z = 543, 545, 547 [M+H]+
(103) [(3,5-dichloro-phenylsulphonyl)-(5-{[6-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl]-aminocarbonyl}-naphthalen-1-yl)-amino]-acetic acid H
N
I
O N N
O
HO N, 0 ci O
ci Rf value: 0.70 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
(104) [(3,5-dichloro-phenylsulphonyl)-(5-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-aminocarbonyl}-naphthalen-1-yl)-amino]-acetic acid N
H
O N I NH
HO'N, '' ci S
O
CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
(105) {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid N
H
O N I N
O
HO~N~ ' CI
O
CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(106) {(3,5-dichloro-phenylsulphonyl)-[5-({6-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-3-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid N
H O N N I
O
HO"U~N, O CI
O
CI
io Rf value: 0.70 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(107) [(3,5-dichloro-phenylsulphonyl)-(5-{[6-(2-dimethylamino-ethylamino)-pyridin-3-ylmethyl]-aminocarbonyl}-naphthalen-2-yl)-amino]-acetic acid H
NN
I
I
O H N
HOMO
N
0=s=0 ciJ CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
(108) {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-am inocarbonyl)-naphthalen-2-yl]-amino}-acetic acid N
H I
O N N' 'N~
HO T, N
o=s=o Cl CI
io Rf value: 0.70 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(109) {(3,5-dichloro-phenylsulphonyl)-[5-({6-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-3-ylmethyl}-am inocarbonyl)-naphthalen-2-yl]-amino}-acetic acid / N
O N I
H0_0 N
0=s=0 ciJ CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 644, 646, 648 [M+H]+
(110) [(3,5-dichloro-phenylsulphonyl)-(5-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-carbamoyl}-naphthalen-2-yl)-amino]-acetic acid N
H I
O N N' 'N~
H
N
o=s=o Cl CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), 1o acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 630, 632, 634 [M+H]+
(111) {(3,5-dichloro-phenylsulphonyl)-[6-(4-piperazin-1-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetic acid N
o=s=o CI I CI
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 572, 574, 576 [M+H]+
(112) {(3,5-dichloro-phenylsulphonyl)-[5-(4-piperazin-1-yl-pyrimidin-2-yl)-naphthalen-1-yl]-amino}-acetic acid H
N
N ~N
O
CI
Rf value: 0.73 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 572, 574, 576 [M+H]+
(113) {(3,5-dichloro-phenylsulphonyl)-[6-(2-morpholin-4-yl-pyrimidin-4-yl)-naphthalen-2-yl]-amino}-acetic acid N
HO O / N
N
O=s=O
CI I CI
Rf value: 0.45 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI-): m/z = 571, 573, 575 [M-H]-(114) [(3,5-dichloro-phenylsulphonyl)-(6-{4-[N-(2-dimethylamino-ethyl)-N-methyl-amino]-pyrimidin-2-yl}-naphthalen-2-yl)-amino]-acetic acid HO O N I N_ N
O=s=0 N
ciJ CI
Rf value: 0.68 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 588, 590, 592 [M+H]+
(115) {(3,5-dichloro-phenylsulphonyl)-[5-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-1-yl]-amino}-acetic acid ~o NJ
N ~N
O
HO N 0 O ci CI
Rf value: 0.15 (silica gel, methylene chloride/methanol = 95:5) io Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(116) ((3,5-dichloro-phenylsulphonyl)-{6-[4-(2-dimethylamino-ethylamino)-pyrimid in-2-yl]-naphthalen-2-yl}-amino)-acetic acid H N
O=s=0 N
Cl CI
Rf value: 0.67 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 574, 576, 578 [M+H]+
(117) {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-4-yl)-naphthalen-1-yl]-amino}-acetic acid O
N
O
CI
HON O
CI
Rf value: 0.33 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(118) {(3,5-dichloro-phenylsulphonyl)-[6-(6-morpholin-4-yl-pyridazin-3-yl)-naphthalen-2-yl]-amino}-acetic acid rO
N N NJ
HOMO
N
O=s=0 ciJ CI
Rf value: 0.30 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(119) {(3,5-dichloro-phenylsulphonyl)-[5-(2-morpholin-4-yl-pyrimidin-5-yl)-naphthalen-1-yl]-amino}-acetic acid O
N
N N
I /
O
HON` SO CI
/
O
CI
Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(120) ((3,5-dichloro-phenylsulphonyl)-{6-[5-(2-dimethylamino-ethylamino)-pyrazin-2-yl]-naphthalen-2-yl}-amino)-acetic acid H
NYN
J
HOMO N
N
O=s=0 ciJ CI
Rf value: 0.58 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) io Mass spectrum (ESI+): m/z = 574, 576, 578 [M+H]+
(121) ((3,5-dichloro-phenylsulphonyl)-{6-[6-(2-dimethylamino-ethylamino)-pyridazin-3-yl]-naphthalen-2-yl}-amino)-acetic acid H
N N N
HOMO
N
O=s=0 ciJ Cl Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 574, 576, 578 [M+H]+
(122) {(3,5-dichloro-phenylsulphonyl)-[6-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetic acid N
H00 ~N
N
O=s=0 ciJ CI
Rf value: 0.45 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(123) {(3,5-dichloro-phenylsulphonyl)-[6-(5-morpholin-4-yl-pyrazin-2-yl)-naphthalen-2-yl]-amino}-acetic acid ro /N J
N I
HOMO N
N \ \
O=s=0 ciJ Cl Rf value: 0.36 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573, 575, 577 [M+H]+
(124) [(3,5-dichloro-phenylsulphonyl)-quinolin-8-yl-amino]-acetic acid O
~ g, CI
HON~
I
CI
Rf value: 0.50 (silica gel, methylene chloride/methanol = 15:1) Mass spectrum (ESI+): m/z = 411, 413, 415 [M+H]+
(125) [(3,5-dichloro-phenylsuIphonyl)-(6-methoxy-quinolin-8-yl)-amino]-acetic acid I
O
O N
HO'N , / CI
o I
CI
Rf value: 0.60 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 60:40:1) io Mass spectrum (ESI+): m/z = 441, 443, 445 [M+H]+
Example 4 Coated tablets containing 75 mg of active substance 1 tablet core contains:
active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hyd roxypropyl methylcel I u lose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvin-ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate.
This granulate is compressed in a tablet-making machine to form tablets of the desired shape.
Weight of core: 230 mg die: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.
Weight of coated tablet: 245 mg.
Example 5 Tablets containing 100 mg of active substance Composition:
1 tablet contains:
active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50 C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
Example 6 Tablets containing 150 mg of active substance io Composition:
1 tablet contains:
active substance 50.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45 C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
Weight of tablet: 300 mg die: 10 mm, flat Example 7 Hard gelatine capsules containing 150 mg of active substance 1 capsule contains:
active substance 150.0 mg corn starch (dried approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg Preparation:
The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.
Example 8 Suppositories containing 150 mg of active substance 1 suppository contains:
active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg Preparation:
After the suppository mass has been melted the active substance is homogeneously 3o distributed therein and the melt is poured into chilled moulds.
Example 9 Suspension containing 50 mg of active substance 100 ml of suspension contain:
active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. Water ad 100 ml Preparation:
The distilled water is heated to 70 C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air.
5 ml of suspension contain 50 mg of active substance.
Example 10 Ampoules containing 10 mg active substance Composition:
active substance 10.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
Example 11 Ampoules containing 50 mg of active substance Composition:
active substance 50.0 mg 0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
Claims (14)
1. Compounds of general formula wherein R a denotes H, a group of formula or a C1-6-alkyl group, which may be substituted by C1-6-alkyl-carbonyloxy, C1-6-alkoxy-carbonyloxy, C1-6-alkoxy, hydroxy, amino, aminocarbonyl or amino-C2-3-alkyloxy, wherein in each case one or two of the hydrogen atoms present on the nitrogen may be replaced independently of one another by a C1-3-alkyl group, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkyloxy or heterocycloalkyl-C1-3-alkyloxy, R b and R c each independently of one another denotes H, halogen, C1-3-alkyl, alkenyl, C2-3-alkynyl, C1-3-perfluoroalkyl, C1-3-alkoxy, C1-3-perfluoroalkoxy, while in each case only one of the groups R b and R c may represent H, A denotes CH or N, while a total of not more than four nitrogen atoms may be present in the bicyclic system, Z denotes CH, CF or N, R d and R e independently of one another denote H, halogen, cyano, hydroxy, nitro, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-fluoroalkyl, C1-6-perfluoroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6-alkoxy, C1-6-fluoroalkoxy, C1-6-perfluoroalkoxy, C3-7-cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, C1-6-alkylsulphanyl, C3-7-cycloalkylsulphanyl or a group selected from among R1R2N, R1R2N-CO, R1R2N-CO-NR3, R1R2N-SO, R1R2N-SO2, R1R2N-SO2-NR3, R4-CO, R4-CO-NR3, R5-SO, R5-SO-NR3, R5-SO2, R5-SO2-NR3- and R5-CO-O-, wherein R1 denotes H, C1-6-alkyl, C3-7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R2 denotes H, C1-6-alkyl, C3-7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, R3 denotes H, C1-6-alkyl or C3-7-cycloalkyl, R4 denotes C1-6-alkyl, C3-7,-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, or C1-6-alkyloxy and R5 denotes C1-6-alkyl, C3-7-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and R f denotes H, halogen, C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, C1-3-perfluoroalkyl, C1-3-alkoxy, C1-3-perfluoroalkoxy or cyano, while the groups contained in the C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C1-6-alkyloxy and C3-7-cycloalkyloxy groups mentioned hereinbefore for R d, R
e, R f as well as R1 to R5 may each be di- or trisubstituted independently of one another in the carbon skeleton by a group selected from among cyano, hydroxy, C3-7-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6-alkoxy, C1-6-perfluoroalkoxy, C3-7-cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy and a group selected from among R6R7N, R6R7N-CO, R6R7N-CO-NR8, R6R7N-SO2-NR8, R9-CO, R9-CO-NR8, R10-SO2, R10-SO2-NR8- and R10-CO-O, wherein R6 denotes H, C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, R7 denotes H, C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, R8 denotes H, C1-4-alkyl, C3-6-cycloalkyl or C3-6-cycloalkyl-C1-4-alkyl, R9 denotes C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl, heteroaryl-C1-4-alkyl, hydroxy or C1-4-alkyloxy and R10 denotes C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, while the above-mentioned substituents must not be bound to a common carbon atom and heteroatoms must be separated from one another by at least two carbon atoms, and the aryl, heteroaryl, aryloxy and heteroaryloxy groups contained in the groups mentioned hereinbefore for R d, R e as well as R1 to R5 may each be di- or trisubstituted independently of one another in the carbon skeleton by a group selected from among halogen, cyano, hydroxy, nitro, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, C1-6-perchloroalkyl, C1-6-fluoroalkyl, perfluoroalkyl, C1-6-alkoxy, C1-6-fluoroalkoxy, C1-6-perfluoroalkoxy, C3-7-cyclo-alkyloxy, C3-7-cycloalkyl-C1-4-alkyloxy, heterocycloalkyloxy, heterocycloalkyl-C1-4-alkyloxy C1-6-alkylsulphanyl, C3-7-cycloalkylsulphanyl, and a group selected from among R6R7N, R6R7N-CO, R6R7N-CO-NR8, R6R7N-SO, R6R7N-SO2, R6R7N-SO2-NR8, R9-CO, R9-CO-NR8, R10-SO, R10-SO-NR8, R10-SO2, R10-SO2-NR8- and R10-CO-O, while R6 to R10 are as hereinbefore defined as well as the physiologically acceptable salts thereof.
e, R f as well as R1 to R5 may each be di- or trisubstituted independently of one another in the carbon skeleton by a group selected from among cyano, hydroxy, C3-7-cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6-alkoxy, C1-6-perfluoroalkoxy, C3-7-cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy and a group selected from among R6R7N, R6R7N-CO, R6R7N-CO-NR8, R6R7N-SO2-NR8, R9-CO, R9-CO-NR8, R10-SO2, R10-SO2-NR8- and R10-CO-O, wherein R6 denotes H, C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, R7 denotes H, C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, R8 denotes H, C1-4-alkyl, C3-6-cycloalkyl or C3-6-cycloalkyl-C1-4-alkyl, R9 denotes C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl, heteroaryl-C1-4-alkyl, hydroxy or C1-4-alkyloxy and R10 denotes C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, while the above-mentioned substituents must not be bound to a common carbon atom and heteroatoms must be separated from one another by at least two carbon atoms, and the aryl, heteroaryl, aryloxy and heteroaryloxy groups contained in the groups mentioned hereinbefore for R d, R e as well as R1 to R5 may each be di- or trisubstituted independently of one another in the carbon skeleton by a group selected from among halogen, cyano, hydroxy, nitro, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, C1-6-perchloroalkyl, C1-6-fluoroalkyl, perfluoroalkyl, C1-6-alkoxy, C1-6-fluoroalkoxy, C1-6-perfluoroalkoxy, C3-7-cyclo-alkyloxy, C3-7-cycloalkyl-C1-4-alkyloxy, heterocycloalkyloxy, heterocycloalkyl-C1-4-alkyloxy C1-6-alkylsulphanyl, C3-7-cycloalkylsulphanyl, and a group selected from among R6R7N, R6R7N-CO, R6R7N-CO-NR8, R6R7N-SO, R6R7N-SO2, R6R7N-SO2-NR8, R9-CO, R9-CO-NR8, R10-SO, R10-SO-NR8, R10-SO2, R10-SO2-NR8- and R10-CO-O, while R6 to R10 are as hereinbefore defined as well as the physiologically acceptable salts thereof.
2. Compounds of general formula (I) according to claim 1, wherein the bicyclic heteroaromatic group denotes naphthalene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, [1,5]naphthyridine, [1,8]naphthyridine, pyrido[3,2-d]pyrimidine, pyrimido[5,4-d]pyrimidine, or pteridine, and R a to R f, R1 to R10, A and Z are defined as in claim 1, with the proviso that at least one of the groups R d and R e denotes H, halogen or C1-3-alkyl, as well as the physiologically acceptable salts thereof.
3. Compounds of general formula (I) according to claim 2, wherein the bicyclic heteroaromatic group denotes naphthalene, quinoline, quinazoline, quinoxaline or cinnoline, R a denotes H, a group of formula or a C1-4-alkyl group, which may be substituted by C1-4-alkoxy, hydroxy, di-(C1-3-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or 4-methyl-piperazin-1-yl, R b and R c independently of one another denote chlorine, bromine or C1-2-alkyl, Z denotes CH or N, R d denotes H, halogen, cyano, hydroxy, nitro, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, aryl-C2-3-alkynyl, C1-4-fluoroalkyl, C1-4-perfluoroalkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl, heteroaryl-C1-4-alkyl, C1-4-alkoxy, C1-4-fluoroalkoxy, C1-4-perfluoroalkoxy, C3-6-cycloalkyloxy, C3-6-cycloalkyl-C1-4-alkyloxy, heterocycloalkyloxy, heterocycloalkyl-C1-4-alkoxy, aryloxy, aryl-C1-4-alkyloxy, heteroaryloxy, heteroaryl-C1-4-alkyloxy, C1-4-alkylsulphanyl or C3-6-cyclo-alkylsulphanyl, while the aryl and heteroaryl groups contained in the groups mentioned hereinbefore for R d may optionally be substituted by halogen, C1-3-alkyl, trichloromethyl, phenyl, phenyl-C1-3-alkyl, hydroxy, C1-3-alkoxycarbonyl, phenyloxy-C1-3-alkyl, phenylsulphonyl-C1-3-alkyl, morpholin-4-yl-C1-3-alkyl, cyano, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, amino-C1-3-alkylamino, C1-3-alkylamino-C1-3-alkylamino, di-(C1-3-alkyl)-amino-C1-3-alkylamino, N-(amino-C1-3-alkyl)-N-(C1-3-alkyl)-amino, N-(C1-3-alkylamino-C1-3-alkyl)-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, morpholin-4-yl, piperazin-1-yl or 4-(C1-3-alkyl)-piperazin-1-yl, or a group selected from among R1R2N, R1R2N-CO, R1R2N-CO-NR3, R1R2N-SO, R1R2N-SO2, R1R2N-SO2-NR3, R4-CO, R4-CO-N R3, R5-SO, R5-SO-NR3, R5-SO2- and R5SO2-NR3, wherein R1 denotes H, C1-4-alkyl, hydroxy-C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalky-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, R2 denotes H, C1-4-alkyl, hydroxy-C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalky-C1-4-alkyl, heterocycloalkyl, heterocycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, R3 denotes H, C1-4-alkyl, C3-6-cycloalkyl or C3-6-cycloalkyl-C1-4-alkyl, R4 denotes C1-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-4-alkyl, heterocycloalkyl, aryl, aryl-C1-4-alkyl, heteroaryl, heteroaryl-C1-4-alkyl, hydroxy or C1-4-alkyloxy and R5 denotes C1-4-alkyl, C3-6-cycloalkyl, heterocycloalkyl, aryl, aryl-C1-4-alkyl, heteroaryl or heteroaryl-C1-4-alkyl, while the aryl and heteroaryl groups contained in the groups mentioned hereinbefore for R1 to R5 may optionally be substituted by halogen, cyano, C1-3-alkoxy, C1-3-alkoxycarbonyl, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, morpholin-4-ylcarbo-nyl, piperazin-1-ylcarbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, amino-C1-3-alkyl, amino-C1-3-alkylamino, C1-3-alkylamino-C1-3-alkyl-amino, di-(C1-3-alkyl)-amino-C1-3-alkylamino, N-(amino-C1-3-alkyl)-N-(C1-3-alkyl)-amino, N-(C1-3-alkylamino-C1-3-alkyl)-N-(C1-3-alkyl)-amino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, R e has the meaning given herein before for R d, with the proviso that at least one of the groups R d and R e must be H, halogen or C1-3-alkyl, and R f denotes H or C1-3-alkyl, as well as the physiologically acceptable salts thereof.
4. Compounds of general formula (I) according to claim 3, wherein the bicyclic heteroaromatic group of general formula (II) denotes naphthalene or quinoline, R a denotes H or a C1-4-alkyl group optionally substituted by a di-(C1-3-alkyl)-amino group, R b and R c independently of one another denote chlorine, bromine or C1-2-alkyl, Z denotes CH, R d denotes H, or, if R e denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1-3-alkoxy, 5-methyl-[1,2,4]oxadiazolyl, aminocarbonyl, wherein a hydrogen atom may be replaced by a C1-3-alkyl group and the second hydrogen atom may be replaced independently thereof by a C1-3-alkyl, phenyl or phenyl-C1-3-alkyl group, and amino, wherein a hydrogen atom may be replaced by a C1-3-alkyl group and the second hydrogen atom may be replaced independently thereof by a C1-3-alkyl or a phenylsulphonyl group, R e denotes H, or, if R d denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1-3-alkyl, C1-3-alkoxy, furanyl, oxazolyl, isoxazolyl, which may be substituted in each case by one or two C1-3-alkyl groups, [1,2,4]oxadiazolyl, which may be substituted by C1-3-alkyl, trichloromethyl, phenyl, benzyl, hydroxy, C1-3-alkoxycarbonyl, phenyloxymethyl, phenyl-sulphonylmethyl or morpholin-4-ylmethyl,
5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, which may be substituted by C1-3-alkyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, which may be substituted in each case by C1-3-alkyl, cyano, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino-C1-3-alkylamino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-alkyl)-amino, morpholin-4-yl or piperazin-1-yl, pyrrolidin-1-ylcarbonyl, 3,4-dihydro-1H-isoquinolin-2-ylcarbonyl, and a group of formula R1R2N-CO, R1R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1-3-alkyl, hydroxy-C1-3-alkyl, C3-6-cycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, pyridinyl or pyridinyl-C1-3-alkyl, R2 denotes H or C1-3-alkyl, R3 denotes H or C1-3-alkyl, and R4 denotes C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, pyridinyl or pyridinyl-C1-3-alkyl, while the phenyl and pyridinyl groups contained in R1 to R4 may optionally be substituted by chlorine, cyano, methoxy, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, aminomethyl, di-(C1-3-alkyl)-amino-C1-3-alkylamino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, and R f denotes H or C1-3-alkyl, as well as the physiologically acceptable salts thereof.
5. Compounds of general formula (I) according to claim 4, wherein the bicyclic heteroaromatic group of formula (II) is naphthalene or quinoline, R a denotes H, R b and R c independently of one another denote chlorine, bromine or methyl, Z denotes CH, R d denotes H, or, if R e denotes H, it may also denote a group selected from among C1-2-alkoxy, 5-methyl-[1,2,4]oxadiazole, N-phenylsulphonyl-N-methyl-amino, N-methyl-N-phenyl-aminocarbonyl, N-benzyl-aminocarbonyl and N-benzyl-N-methyl-aminocarbonyl, R e denotes H, or, if R d denotes H, it may also denote a group selected from among methoxy, furanyl, oxazolyl, isoxazolyl, 3,5-dimethyl-isoxazole, 3-methyl-[1,2,4]oxadiazolyl, 5-methyl-[1,2,4]oxadiazolyl, 5-trichloromethyl-[1,2,4]oxadia-zolyl, 5-isopropyl-[1,2,4]oxadiazolyl, 3-phenyl-[1,2,4]oxadiazolyl, 5-phenyl-[1,2,4]oxadiazolyl, 3-benzyl-[1,2,4]oxadiazolyl, 5-benzyl-[1,2,4]oxadiazolyl, 5-hydroxy-[1,2,4]oxadiazolyl, 3-ethoxycarbonyl-[1,2,4]oxadiazolyl, 3-phenyl-oxymethyl-[1,2,4]oxadiazolyl, 3-phenylsulphonylmethyl-[1,2,4]oxadiazolyl, 5-(morpholin-4-ylmethyl)-[1,2,4]oxadiazolyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazo-lyl, 4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, pyridinyl, pyrimidinyl, 4-(piperazin-1-yl)-pyrimidinyl, 2-(morpholin-4-yl)-pyrimidinyl, 4-(morpholin-4-yl)-pyrimidinyl, 4-(2-dimethylamino-ethylamino)-pyrimidinyl, 4-[N-(2-dimethylamino-ethyl)-N-methyl-amino]-pyrimidinyl, 5-(morpholin-4-yl)-pyrazin-2-yl, 5-(2-dimethylamino-ethylamino)-pyrazin-2-yl, 6-(morpholin-4-yl)-pyridazin-3-yl, 6-(2-dimethylamino-ethylamino)-pyridazin-3-yl, pyrrolidin-1-ylcarbonyl, 3,4-dihydro-1H-isoquinolin-2-ylcarbonyl, and a group of formula n R1R2N-CO, R1R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1-3-alkyl, hydroxyethyl, cyclohexylmethyl, phenyl, benzyl, 2-phenyl-ethyl, pyridinyl or pyridinylmethyl, R2 denotes H or methyl, R3 denotes H
and R4 denotes phenyl, benzyl, 2-phenyl-ethyl or pyridinyl, while the phenyl, benzyl and 2-phenyl-ethyl groups contained in R1 and R4 may be substituted by a cyano, methoxy, carboxy, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl or aminomethyl group and the pyridinyl and pyridinylmethyl groups contained in R1 and R4 may be substituted by a chlorine atom or a 2-dimethylamino-ethylamino or N-(2-dimethylamino-ethyl)-N-(methyl)-amino group, and R f denotes H, as well as the physiologically acceptable salts thereof.
5. Compounds of general formula (I) according to claim 4, wherein the bicyclic heteroaromatic group of formula (II) is naphthalene or quinoline, R a denotes H, R b and R c independently of one another denote chlorine, bromine or methyl, Z denotes CH, R d denotes H, or, if R e denotes H, it may also denote a group selected from among C1-2-alkoxy, 5-methyl-[1,2,4]oxadiazole, N-phenylsulphonyl-N-methyl-amino, N-methyl-N-phenyl-aminocarbonyl, N-benzyl-aminocarbonyl and N-benzyl-N-methyl-aminocarbonyl, R e denotes H, or, if R d denotes H, it may also denote a group selected from among methoxy, furanyl, oxazolyl, isoxazolyl, 3,5-dimethyl-isoxazole, 3-methyl-[1,2,4]oxadiazolyl, 5-methyl-[1,2,4]oxadiazolyl, 5-trichloromethyl-[1,2,4]oxadia-zolyl, 5-isopropyl-[1,2,4]oxadiazolyl, 3-phenyl-[1,2,4]oxadiazolyl, 5-phenyl-[1,2,4]oxadiazolyl, 3-benzyl-[1,2,4]oxadiazolyl, 5-benzyl-[1,2,4]oxadiazolyl, 5-hydroxy-[1,2,4]oxadiazolyl, 3-ethoxycarbonyl-[1,2,4]oxadiazolyl, 3-phenyl-oxymethyl-[1,2,4]oxadiazolyl, 3-phenylsulphonylmethyl-[1,2,4]oxadiazolyl, 5-(morpholin-4-ylmethyl)-[1,2,4]oxadiazolyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazo-lyl, 4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, pyridinyl, pyrimidinyl, 4-(piperazin-1-yl)-pyrimidinyl, 2-(morpholin-4-yl)-pyrimidinyl, 4-(morpholin-4-yl)-pyrimidinyl, 4-(2-dimethylamino-ethylamino)-pyrimidinyl, 4-[N-(2-dimethylamino-ethyl)-N-methyl-amino]-pyrimidinyl, 5-(morpholin-4-yl)-pyrazin-2-yl, 5-(2-dimethylamino-ethylamino)-pyrazin-2-yl, 6-(morpholin-4-yl)-pyridazin-3-yl, 6-(2-dimethylamino-ethylamino)-pyridazin-3-yl, pyrrolidin-1-ylcarbonyl, 3,4-dihydro-1H-isoquinolin-2-ylcarbonyl, and a group of formula n R1R2N-CO, R1R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1-3-alkyl, hydroxyethyl, cyclohexylmethyl, phenyl, benzyl, 2-phenyl-ethyl, pyridinyl or pyridinylmethyl, R2 denotes H or methyl, R3 denotes H
and R4 denotes phenyl, benzyl, 2-phenyl-ethyl or pyridinyl, while the phenyl, benzyl and 2-phenyl-ethyl groups contained in R1 and R4 may be substituted by a cyano, methoxy, carboxy, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl or aminomethyl group and the pyridinyl and pyridinylmethyl groups contained in R1 and R4 may be substituted by a chlorine atom or a 2-dimethylamino-ethylamino or N-(2-dimethylamino-ethyl)-N-(methyl)-amino group, and R f denotes H, as well as the physiologically acceptable salts thereof.
6. Compounds of general formula wherein R b and R c each denote chlorine, R d denotes H, or, if R e denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1-3-alkyl, C1-3-alkoxy, 5-methyl-[1,2,4]oxadiazolyl, aminocarbonyl, wherein a hydrogen atom may be replaced by a C1-3-alkyl group and the second hydrogen atom may be replaced independently thereof by a C1-3-alkyl, phenyl or phenyl-C1-3-alkyl group, and amino, wherein a hydrogen atom may be replaced by a C1-3-alkyl group and the second hydrogen atom may be replaced independently thereof by a C1-3-alkyl or a phenylsulphonyl group, and R e denotes H, or, if R d denotes H, it may also denote a group selected from among fluorine, chlorine, bromine, cyano, C1-3-alkyl, C1-3-alkoxy, furanyl, oxazolyl, isoxazolyl, which may be substituted in each case by one or two C1-3-alkyl groups, [1,2,4]oxadiazolyl, which may be substituted by C1-3-alkyl, trichloromethyl, phenyl, benzyl, hydroxy, C1-3-alkoxycarbonyl, phenyloxymethyl, phenyl-sulphonylmethyl or morpholin-4-ylmethyl, 5-oxo-4,5-dihydro-[1,2,4]oxadiazolyl, which may be substituted by C1-3-alkyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, which may be substituted in each case by C1-3-alkyl, cyano, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino-C1-3-alkylamino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-alkyl)-amino, morpholin-4-yl or piperazin-1-yl, pyrrolidin-1-ylcarbonyl, 3,4-dihydro-1H-isoquinolin-2-ylcarbonyl, and a group of formula n R1R2N-CO, R1R2N-CO-NR3 or R4CONR3, wherein R1 denotes H, C1-3-alkyl, hydroxy-C1-3-alkyl, C3-6-cycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, pyridinyl or pyridinyl-C1-3-alkyl, R2 denotes H or C1-3-alkyl, R3 denotes H or C1-3-alkyl, and R4 denotes phenyl, phenyl-C1-3-alkyl, pyridinyl or pyridinyl-C1-3-alkyl, while the phenyl and pyridinyl groups contained in R1 to R4 may optionally be substituted by chlorine, cyano, methoxy, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, aminomethyl, di-(C1-3-alkyl)-amino-C1-3-alkylamino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, as well as the physiologically acceptable salts thereof.
7. The following compounds according to claim 1:
(1) [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (2) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid, (3) {(3,5-dichloro-phenylsulphonyl)-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid, (4) [(5-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (5) [(3,5-dichloro-phenylsulphonyl)-(5-pyrimidin-2-yl-naphthalen-1-yl)-amino]-acetic acid, (6) {(3,5-dichloro-phenylsulphonyl)-[5-(5-morpholin-4-ylmethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid, (7) ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid, (8) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-ureido)-naphthalen-1-yl]-amino}-acetic acid, (9) [[5-(3-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (10) [[5-(2-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenyl-sulphonyl)-amino]-acetic acid, (11) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(piperazin-1-ylcarbonyl)-benzylamino-carbonyl]-naphthalen-1-yl}-amino)-acetic acid, (12) {(3,5-dichloro-phenylsulphonyl)-[5-(4-methylaminocarbonyl-benzylamino-carbonyl)-naphthalen-1-yl]-amino}-acetic acid, (13) {(3,5-dichloro-phenylsulphonyl)-[5-(3-methylaminocarbonyl-benzylamino-carbonyl)-naphthalen-1-yl]-amino}-acetic acid, (14) {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid, (15) ((3,5-dichloro-phenylsulphonyl)-{6-[5-(2-dimethylamino-ethylamino)-pyrazin-2-yl]-naphthalen-2-yl}-amino)-acetic acid, (16) {(3,5-dichloro-phenylsulphonyl)-[6-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetic acid, (17) [(3,5-dichloro-phenylsulphonyl)-quinolin-8-yl-amino]-acetic acid and (18) [(3,5-dichloro-phenylsulphonyl)-(6-methoxy-quinolin-8-yl)-amino]-acetic acid, as well as the physiologically acceptable salts thereof.
(1) [[5-(4-aminocarbonyl-benzylaminocarbonyl)-naphthalen-2-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (2) {(3,5-dichloro-phenylsulphonyl)-[6-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid, (3) {(3,5-dichloro-phenylsulphonyl)-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-naphthalen-2-yl]-amino}-acetic acid, (4) [(5-benzylaminocarbonyl-naphthalen-1-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (5) [(3,5-dichloro-phenylsulphonyl)-(5-pyrimidin-2-yl-naphthalen-1-yl)-amino]-acetic acid, (6) {(3,5-dichloro-phenylsulphonyl)-[5-(5-morpholin-4-ylmethyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-yl]-amino}-acetic acid, (7) ((3,5-dichloro-phenylsulphonyl)-{5-[(pyridin-3-ylmethyl)-aminocarbonyl]-naphthalen-1-yl}-amino)-acetic acid, (8) {(3,5-dichloro-phenylsulphonyl)-[5-(3-phenyl-ureido)-naphthalen-1-yl]-amino}-acetic acid, (9) [[5-(3-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-acetic acid, (10) [[5-(2-cyano-benzylaminocarbonyl)-naphthalen-1-yl]-(3,5-dichloro-phenyl-sulphonyl)-amino]-acetic acid, (11) ((3,5-dichloro-phenylsulphonyl)-{5-[4-(piperazin-1-ylcarbonyl)-benzylamino-carbonyl]-naphthalen-1-yl}-amino)-acetic acid, (12) {(3,5-dichloro-phenylsulphonyl)-[5-(4-methylaminocarbonyl-benzylamino-carbonyl)-naphthalen-1-yl]-amino}-acetic acid, (13) {(3,5-dichloro-phenylsulphonyl)-[5-(3-methylaminocarbonyl-benzylamino-carbonyl)-naphthalen-1-yl]-amino}-acetic acid, (14) {(3,5-dichloro-phenylsulphonyl)-[5-({2-N-[(2-dimethylamino-ethyl)-N-methyl-amino]-pyridin-4-ylmethyl}-aminocarbonyl)-naphthalen-1-yl]-amino}-acetic acid, (15) ((3,5-dichloro-phenylsulphonyl)-{6-[5-(2-dimethylamino-ethylamino)-pyrazin-2-yl]-naphthalen-2-yl}-amino)-acetic acid, (16) {(3,5-dichloro-phenylsulphonyl)-[6-(4-morpholin-4-yl-pyrimidin-2-yl)-naphthalen-2-yl]-amino}-acetic acid, (17) [(3,5-dichloro-phenylsulphonyl)-quinolin-8-yl-amino]-acetic acid and (18) [(3,5-dichloro-phenylsulphonyl)-(6-methoxy-quinolin-8-yl)-amino]-acetic acid, as well as the physiologically acceptable salts thereof.
8. Physiologically acceptable salts of the compounds according to claims 1 to with inorganic or organic acids or bases.
9. Compounds according to one of claims 1 to 8 for use as pharmaceutical compositions.
10. Compounds according to one of claims 1 to 8 for the treatment of type I
and type II diabetes mellitus.
and type II diabetes mellitus.
11. Pharmaceutical compositions, containing a compound according to at least one of Claims 1 to 7 or a salt according to claim 8 optionally together with one or more inert carriers and/or diluents.
12. Use of a compound according to at least one of Claims 1 to 7 or a salt according to claim 8 for preparing a pharmaceutical composition that is suitable for the treatment of type I and type II diabetes mellitus.
13. Process for preparing a pharmaceutical composition according to claim 11, characterised in that a compound according to at least one of claims 1 to 7 or a salt according to claim 8 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
14. Process for preparing the compounds of general formula (I) according to claims 1 to 8, characterised in that a compound of general formula (IV) wherein R b, R c, Z and A are defined as in claim 1 and R d', R e' and R f' either have the meaning given for R d, R e and R f in claim 1 or denote groups that can be converted into R d, R e and R f by known methods of synthesis, is alkylated by means of a suitable acetic acid ester derivative of general formula R a-O-(CO)-CH2-X, wherein R a" either has the meaning given for R a in claim 1 or denotes a group which may be converted into R a by known methods of synthesis and X denotes a leaving group, and if desired any protective group used to protect reactive groups during the reactions is cleaved afterwards or simultaneously and/or a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with an inorganic or organic acid or base.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102008019838A DE102008019838A1 (en) | 2008-04-19 | 2008-04-19 | New arylsulfonylglycine derivatives, their preparation and their use as pharmaceuticals |
| DE102008019838.2 | 2008-04-19 | ||
| PCT/EP2009/054593 WO2009127723A1 (en) | 2008-04-19 | 2009-04-17 | New arylsulphonylglycine derivatives, the preparation thereof and their use as medicaments |
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| Publication Number | Publication Date |
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| CA2721785A1 true CA2721785A1 (en) | 2009-10-22 |
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| CA2721785A Abandoned CA2721785A1 (en) | 2008-04-19 | 2009-04-17 | New arylsulphonylglycine derivatives, the preparation thereof and their use as medicaments |
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| Country | Link |
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| US (1) | US20110269761A1 (en) |
| EP (1) | EP2279173A1 (en) |
| JP (1) | JP2011518138A (en) |
| CA (1) | CA2721785A1 (en) |
| DE (1) | DE102008019838A1 (en) |
| WO (1) | WO2009127723A1 (en) |
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| WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
| US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
| TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
| TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
| CN103906733A (en) | 2011-06-24 | 2014-07-02 | 安姆根有限公司 | TRMP8 antagonists and their use in treatments |
| US8778941B2 (en) | 2011-06-24 | 2014-07-15 | Amgen Inc. | TRPM8 antagonists and their use in treatments |
| WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| CA2865511A1 (en) | 2012-03-07 | 2013-09-12 | Institute Of Cancer Research: Royal Cancer Hospital (The) | 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use |
| US8952009B2 (en) | 2012-08-06 | 2015-02-10 | Amgen Inc. | Chroman derivatives as TRPM8 inhibitors |
| EP2882713A4 (en) | 2012-08-07 | 2016-01-06 | Univ Washington Ct Commerciali | Fluorescent dyes and related methods |
| EP3044221B1 (en) | 2013-09-11 | 2018-02-21 | Institute of Cancer Research: Royal Cancer Hospital (The) | 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use |
| US11274078B2 (en) * | 2017-04-10 | 2022-03-15 | Jianyou Shi | Drug for treating tumor diseases and having antibacterial antivirus anti-inflammatory effects |
| CN112724052B (en) * | 2021-01-21 | 2021-09-07 | 南京艾美斐生物医药科技有限公司 | GPR101 protein receptor inhibitor and preparation and application thereof |
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| DE3837926A1 (en) * | 1988-11-09 | 1990-05-17 | Basf Ag | HERBICIDES THAT HAVE 2- (4-HETEROARYLOXY) - OR 2- (4-ARYLOXY) -PHENOXYROCYCLE OR -PROPIONIC ACID DERIVATIVES AND / OR CYCLOHEXENONE DERIVATIVES AS AN HERBICIDE ACTIVE INGREDIENT ADHESIVE INTENSIVE ADMINISTRATIVE INTENSIVE |
| US5112821A (en) * | 1989-05-16 | 1992-05-12 | Merrell Dow Pharmaceuticals Inc. | Excitatory amino acid antagonists which are certain thienopyridives |
| ZA903588B (en) * | 1989-05-16 | 1991-02-27 | Merrell Dow Pharma | Excitatory amino acid antagonists |
| DE69730137T2 (en) * | 1996-06-20 | 2005-07-14 | Schering Corp. | NAPHTHYRIDINES INFLUENCING THE RECEPTOR IL-4 AND THE FACTOR G-CSF |
| DE19754490A1 (en) * | 1997-12-09 | 1999-06-10 | Boehringer Ingelheim Pharma | By an aminocarbonyl substituted bicyclic, their preparation and their use as medicaments |
| YU98003A (en) * | 2001-06-11 | 2006-03-03 | Biovitrum Ab. | Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes |
| JPWO2003059870A1 (en) * | 2002-01-17 | 2005-05-19 | 塩野義製薬株式会社 | N-substituted sulfonamide derivative and drug for preventing or treating diabetes containing the same |
| AU2003274373A1 (en) * | 2002-10-24 | 2004-05-13 | Sterix Limited | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 and type 2 |
| WO2004098588A1 (en) * | 2003-05-09 | 2004-11-18 | Laboratorios Del Dr. Esteve S.A. | Use of sulphonamide derivatives for the manufacture of a medicament for the prophylaxis and/or treatment of disorders of food ingestion |
| ES2219181B1 (en) * | 2003-05-09 | 2005-12-16 | Laboratorios Del Dr. Esteve, S.A. | USE OF SULFONAMID DERIVATIVES FOR THE MANUFACTURE OF A MEDICINAL PRODUCT FOR PROFILAXIS AND / OR TREATMENT OF FOOD DYSFUNCTIONS. |
| BRPI0510095A (en) * | 2004-04-20 | 2007-10-16 | Transtech Pharma Inc | substituted thiazole and pyrimidine derivatives as melanocortin receptor modulators |
| FR2874011B1 (en) * | 2004-08-03 | 2007-06-15 | Sanofi Synthelabo | SULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| EP1844768A1 (en) * | 2005-01-19 | 2007-10-17 | Dainippon Sumitomo Pharma Co., Ltd. | Aromatic sulfone compound as aldosterone receptor modulator |
| US7994338B2 (en) * | 2006-08-16 | 2011-08-09 | The J. David Gladstone Institutes | Small molecule inhibitors of kynurenine-3-monooxygenase |
| DE102007007751A1 (en) * | 2007-02-16 | 2008-08-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel substituted arylsulfonylglycines, their preparation and their use as pharmaceuticals |
| DE102007012284A1 (en) * | 2007-03-16 | 2008-09-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel substituted arylsulfonylglycines, their preparation and their use as pharmaceuticals |
| DE102007035333A1 (en) * | 2007-07-27 | 2009-01-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel substituted arylsulfonylglycines, their preparation and their use as pharmaceuticals |
| DE102007042154A1 (en) * | 2007-09-05 | 2009-03-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Arylsulfonylaminomethyphosphonsäure derivatives, their preparation and their use as medicaments |
-
2008
- 2008-04-19 DE DE102008019838A patent/DE102008019838A1/en not_active Withdrawn
-
2009
- 2009-04-17 CA CA2721785A patent/CA2721785A1/en not_active Abandoned
- 2009-04-17 WO PCT/EP2009/054593 patent/WO2009127723A1/en active Application Filing
- 2009-04-17 JP JP2011504477A patent/JP2011518138A/en active Pending
- 2009-04-17 US US12/988,452 patent/US20110269761A1/en not_active Abandoned
- 2009-04-17 EP EP09732153A patent/EP2279173A1/en not_active Withdrawn
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| DE102008019838A1 (en) | 2009-12-10 |
| JP2011518138A (en) | 2011-06-23 |
| WO2009127723A1 (en) | 2009-10-22 |
| US20110269761A1 (en) | 2011-11-03 |
| EP2279173A1 (en) | 2011-02-02 |
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